Lipid metabolism, amino acid metabolism, and prostate cancer: a crucial metabolic journey

Abstract

Prostate cancer (PCa) is one of the most common malignancies in males worldwide, and its development and progression involve the regulation of multiple metabolic pathways. Alterations in lipid metabolism affect the proliferation and metastatic capabilities of PCa cells. Cancer cells increase lipid synthesis and regulate fatty acid oxidation to meet their growth and energy demands. Similarly, changes occur in amino acid metabolism in PCa. Cancer cells exhibit an increased demand for specific amino acids, and they regulate amino acid transport and metabolic pathways to fulfill their proliferation and survival requirements. These changes are closely associated with disease progression and treatment response in PCa cells. Therefore, a comprehensive investigation of the metabolic characteristics of PCa is expected to offer novel insights and approaches for the early diagnosis and treatment of this disease.

INTRODUCTION

Prostate cancer (PCa) incidence and progression are strongly associated with age, particularly after puberty when the prostate undergoes gradual growth and development. This can result in an elevation of cell count and metabolic activity, increasing the risk of PCa.1 When many patients are pathologically diagnosed with PCa, it is necessary to determine the extent of tumor spread based on staging to assess prognosis and select appropriate treatment modalities. The tumor node metastasis (TNM) staging of PCa primarily relies on predictive tools such as tumor markers, imaging studies, and diagnostic techniques. In the precancerous stage, it is typically categorized as T1 stage. Subsequently, based on the precancerous lesions, PCa gradually progresses to the T2 stage, at which cancer cells begin to proliferate rapidly and form tumors. However, the cancer cells remain confined to the prostate and have not spread to surrounding tissues and lymph nodes at this stage, making it the ideal treatment period for PCa. Generally, T2 stage is treated with surgery, radiotherapy, or observation. However, if localized PCa is not effectively treated, that is, at the T3 and T4 stages, cancer cells may spread to surrounding tissues and lymph nodes or even to other organs, causing metastatic PCa, which considerably raises the challenge and danger of treatment.2 Therefore, the creation of focused medications and treatments for PCa is critical. Fortunately, since the discovery of the hormone dependence of PCa, androgen deprivation therapy (ADT) has emerged as the most favored treatment option for PCa patients because of its ability to maintain the patient’s sexual function to the greatest extent possible. Due to this, endocrine therapy drugs for PCa have been extensively researched and rapidly developed, mainly including antiandrogen drugs and gonadotropin-releasing hormone receptor (GnRHR) analogs. The new representative antiandrogen drugs mainly include nonsteroidal options such as flutamide, as well as steroidal choices such as abiraterone3,4 (Figure 1).

Figure 1.

History of PCa development. The development process of PCa is classified according to TNM staging, which describes the gradual progression of the tumor. T1 stage represents a tumor that is not detectable by imaging examination, whereas T2 stage shows a tumor confined within the prostate. As the tumor progresses to the T3 stage, it exceeds the prostate capsule. T4 stage tumors invade adjacent prostate tissue and are often accompanied by regional lymph node metastasis in the N1 stage, while M1 stage tumors metastasize to distant locations. Currently, the primary drugs used for treating advanced PCa are androgen-blocking medications, including flutamide, abiraterone, and buserelin. PIA: proliferative inflammatory atrophy; PIN: prostatic intraepithelial neoplasia; TNM: tumor node metastasis; PCa: prostate cancer; PSA: prostate-specific antigen; GnRHR: gonadotropin-releasing hormone receptor.

Although most tumors share common metabolic characteristics, PCa exhibits unique metabolic features that are increasingly being recognized. The close association between tumor metabolism and PCa metabolism has led to the identification of abnormal metabolism in PCa cells as a significant contributor to the disease’s malignant progression and metastasis. While PCa cell metabolism shares similarities with general tumor cell metabolism, it also possesses special properties. Abnormal amino acid metabolism in PCa cells mainly manifests as abnormalities in glutamic acid (Glu) metabolism, which is generated via glutamine (Gln) to meet growth and proliferation needs.5 Furthermore, PCa cells promote cholesterol (CHOL) intake and synthesis, as well as the use of fatty acids for energy metabolism and the formation of membrane lipids.6 These metabolic features of PCa not only add to our understanding of cancer biology but also provide new perspectives and methods for PCa diagnosis and treatment.

This article aims to examine the two primary pathways responsible for the metabolism of PCa: metabolic processes of lipids and amino acids. Additionally, the latest advancements in regulatory signals governing these pathways, including regulatory enzymes, genes, and pathways, will be reviewed. Understanding these latest advances will help us obtain a greater comprehension of the molecular mechanisms and traits that govern tumor metabolism, to find more efficient treatment modalities.

LIPID METABOLISM AND PCA

Lipid metabolism is a complicated set of chemical reactions that occur within cells, involving processes such as fatty acid synthesis, esterification, fatty acid oxidation, and CHOL synthesis. These reactions are essential for maintaining normal cellular physiology.7 Many tumor cells require high levels of lipid metabolism to maintain the energy supply necessary for their rapid proliferation and survival. In liver cancer cells, there is a marked increase in the expression of fatty acid synthase (FAS), which has also been validated in other cancers.8 Furthermore, the content of phospholipids is significantly increased in many tumor cells. Chow et al.9 have demonstrated that the phosphatidylinositol 3-kinase (PI3K) pathway is essential for promoting tumor cell survival and proliferation. Therefore, the disorder of lipid metabolism and the development of tumors are closely intertwined and may impact the biological characteristics of cancer cells, such as proliferation, metastasis, and drug resistance, ultimately affecting the prognosis of the tumor.

ADT can ameliorate the condition of most PCa patients; however, after 18 months to 24 months, almost all patients progress to castration-resistant prostate cancer (CRPC). Despite reduced levels of circulating androgens at the CRPC stage, intratumoral androgen levels remain elevated and are capable of activating the androgen receptor (AR) and its downstream pathways. At this juncture, significant alterations in lipid metabolism occur. Specifically, fatty acid synthase (FASN) continues to play a role not only in the growth of early PCa cells but also in CRPC.10 Leon et al.11 indicate increased expression and enzymatic activity of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, along with reduced expression of ATP citrate lyase (ACLY), leading to the liberation of free CHOL stored in CHOL esters. These liberated CHOL and fatty acids are utilized in steroidogenesis, further exacerbating the changes in lipid metabolism (Figure 2). Consequently, for both the prevention and treatment of PCa, mitigating saturated fatty acid consumption may constitute a pivotal intervention. In the context of PCa, the growth, invasion, and metastasis of cancer cells are all contingent upon lipid metabolism, encompassing constituents such as fatty acids, CHOL, and phospholipids (Table 1).

Figure 2.

Signaling pathways associated with PCa are involved in the regulation of lipid metabolism. Fatty acids are the main component of lipid metabolism. The ACC-regulated fatty acid synthesis pathway results in the remarkable enhancement of fatty acids in PCa cells, which is affected by fatty acid-related metabolic enzymes, including ACLY, FAS, ACC, and SCD. Additionally, in some PCa cells, acetyl-CoA affected by the key enzymes ACAT, HMGCS, and HMGCR will synthesize more CHOL. Lipid metabolism products such as fatty acids, CHOL, and phospholipids ultimately promote the proliferation, invasion, and migration of PCa cells. ADP: adenosine diphosphate; ATP: adenosine triphosphate; ETC: electron transport chain; AMPK: AMP-activated protein kinase; EFA: essential fatty acids; TAG: triacylglycerol; PUFA: polyunsaturated fatty acid; SCD: stearoyl coenzyme A desaturase; SFA: saturated fatty acids; FAS: fatty acid synthase; ACC: acetyl-CoA carboxylase; ACLY: ATP citrate lyase; GP: glycerol phospholipid; CHOL: cholesterol; HMGCR: 3-hydroxy-3-methylglutaryl-coenzyme A reductase; HMGCS: 3-hydroxy-3-methylglutaryl-coenzyme A synthase; ACAT: acyl coenzyme A-cholesterol acyltransferase; AKG: α-ketoglutaric acid; IDH1: isocitrate dehydrogenase soluble; ACSL: long-chain acyl-CoA synthetase; TG: triglyceride; Gln: glutamine; TCA: tricarboxylic acid; GLUT1: glucose transporter 1; 3PG: 3-phosphoglycerate; FADH₂: flavin adenine dinucleotide; NADH: nicotinamide adenine dinucleotide.

Table 1.

Summary of the molecular mechanisms of lipid metabolism regulation in prostate cancer, involving enzymes, genes, and pathways

Lipid	Model	Type	Effects	Mechanisms	Reference
Fatty acids
ACLY	LNCaP, PC-3, C4-2, and LNCaP-Abl cells	In vitro	↓AR	↓ACLY and AMPK signaling	21
	PC-3 and LNCaP cells PC-3 xenograft mice	In vitro In vivo	↑Apoptosis,↓cell growth ↓Tumor size	↓ACLY	22
FAS	LNCaP and C4-2 cells	In vitro	↓Fatty-acid levels, lipid accumulation, PSA, cell growth, migration, invasion, and apoptosis	↓FASN and AR ↑Caspase-dependent pathway	26
	LNCaP, PC3, DU145, and 22Rv1 cells A preclinical mouse model that lacks expression of prostate-specific phosphatase and tensin homolog	In vitro In vivo	↓Cell proliferation, migration, invasion, and growth ↓PCa development, ACC, and fatty acid synthase	↓CAMKK2 ↑AMPK	27
	PC-3, DU145, LNCaP and C4-2 cells C4-2 xenograft mice	In vitro In vivo	↓Cell growth, FASN, and lipid accumulation	↓Acetyltransferase	28
ACC	DU145 and PC-3 cells	In vitro	↓Mitochondrial beta-oxidation, mitochondrial dysfunction, and ATP production ↑Reactive oxygen species	↓De novo fatty acid synthesis, PI3K/AKT signaling, and ACACA	32
	DU145 and LNCaP cells	In vitro	↓ACC1	↓Pin1 ↑Lysosomal pathway	33
FABP5	TMPRSS2:ERG fusion-negative tumors	In vivo	↑FABP5	SPOP and FOXA1 mutations ↑PPAR signaling	36
	PC-3 and MDA-MB-231 cells	In vitro	↑Inflammation and cytokine production, aggressiveness of cells	↑NF-κB signaling pathway	37
SCD	LNCaP, 22Rv1, PC-3, DU145 and CV-1 cells LNCaP xenograft mice	In vitro In vivo	↑PSA and kallikrein-related peptidase 2 ↑Tumor formation and growth	↑SCD and AR transcriptional activity	39
	LNCaP and C4-2 cells LNCaP xenograft mice	In vitro In vivo	↓Lipid synthesis and proliferation of cells ↓Tumor growth	↓SCD1, concentration of phosphatidylinositol tri-phosphate, AKT pathway, AMPK and GSK3α/β	40
	LNCaP and PC-3 cells	In vitro	↓Cell viability and cell cycle in G2 ↑Apoptosis	↓SCD enzymatic activity	41
PPARγ	C4-2 and VCaP cells	In vitro	↓PPARγ	↑AR	45
CHOL
ACAT	PC-3 cells PC-3 xenograft mice	In vitro In vivo	↓Cholesteryl ester storage,↑intracellular free CHOL levels, apoptosis and suppression of proliferation ↓Tumor growth in mice, ↑the length of survival time	↓ACAT-1	56
HMGCS	LNCaP, PC-3, and 22Rv1 cells	In vitro	↓Cell viability and growth	↓HMGCS1 and HMGCR	59
HMGCR	PC3-TxR and PC-3 cells	In vitro	↑The sensitivity of resistant PCa cells to paclitaxel	↓CYP2C8	65
Phospholipids
PI3K/AKT	LNCaP, 22Rv1 and C4-2 cells	In vitro	↓Maspin tumor suppressor	↑MAPK or PI3K/AKT-Rac1 signaling	69

CHOL: cholesterol; ACAT: acyl coenzyme A-CHOL acyltransferase; ACAT-1: acyl coenzyme A-CHOL acyltransferase-1; ACC: acetyl-CoA carboxylase; ACC1: acetyl-coA carboxylase1; ACLY: ATP citrate lyase; AMPK: AMP-activated protein kinase; AR: androgen receptor; CAMKK2: calcium-calmodulin protein kinase kinase 2; CYP2C8: cytochrome P450 2C8; FABP5: fatty acid binding protein 5; FAS: fatty acid synthase; FASN: fatty acid synthase; FOXA1: forkhead box A1; HMGCR: 3-hydroxy-3-methylglutaryl-coenzyme A reductase; HMGCS: 3-hydroxy-3-methylglutaryl-coenzyme A synthase; HMGCS1: 3-hydroxy-3-methylglutaryl-coenzyme A synthase 1; MAPK: mitogen-activated protein kinase; NF-κB: nuclear factor-kappa B; Pin1: prolyl isomerase 1; PPAR: peroxisome proliferators-activated receptors; PPARγ: peroxisome proliferators-activated receptors gamma; PSA: prostate-specific antigen; SCD: stearoyl coenzyme A desaturase; SCD1: stearoyl coenzyme A desaturase1; SPOP: speckle-type poz protein; PCa: prostate cancer; TMPRSS2: transmembrane serine protease 2; ERG: E26 oncogene; ↓: degulation or inhibition; ↑: upregulation or activation

Fatty acids and PCa

Fatty acids constitute a fundamental component of cell membranes, thus rendering them crucial for the normal functionality and structural integrity of cells. Nevertheless, under certain circumstances, an abnormally elevated intake of fatty acids can predispose to tumorigenesis. This propensity arises from the potential disruption of intracellular fatty acid metabolism due to excessive dietary intake, consequently fostering aberrant cellular proliferation and the development of malignant tumors.12 Quantitative mass spectrometry of lipid composition in malignant and benign tissues from PCa patients elucidated changes in PCa lipids, including changes in fatty acid synthesis, elongation, and desaturation.13 Furthermore, it has been observed that African American individuals are more susceptible to PCa and have a higher mortality rate from this cancer compared to European American individuals. Chromatin immunoprecipitation sequencing has revealed a greater number of AR binding sites associated with lipid metabolism and immune response genes in African American patients. This underscores the significance of lipid metabolism as a crucial therapeutic target for treating PCa and provides a potential breakthrough avenue.14

Abnormal fatty acid metabolism is frequent in PCa patients. PCa tissues exhibit elevated levels of insulin-like growth factor (IGF) and fatty acid transport protein (FATP), both of which are receptors and enzymes involved in fatty acid metabolism. In addition, PCa cells demonstrate increased uptake and utilization of fatty acids. Dysregulated fatty acid metabolism is closely linked with various aspects of PCa cell growth, proliferation, metastasis, and prognosis. According to research, dysregulated fatty acid metabolism can disrupt PCa cell signaling pathways, gene expression, and the cell cycle, thereby impacting cell proliferation and metastasis.15 PCa cells display a significant reliance on fatty acid absorption and metabolism, particularly for long-chain fatty acids, which are uncommon in normal cells.16 Through the component ACLY in the catalytic acyl-CoA synthetase, long-chain fatty acids may regulate PCa metabolism, thereby promoting tumor cell growth and proliferation.17 In addition, fatty acids can influence cancer growth by influencing PCa cell survival and apoptosis. Long-chain fatty acids can affect PCa cell survival, leading to cell proliferation and cancer development.18

ACLY

ACLY is an essential enzyme that has critical effects on lipid metabolism and energy metabolism. This enzyme facilitates the conversion of citrate to acetyl-CoA, which is a crucial step in the creation of biological molecules such as fatty acids, CHOL, and isoprenoids. ACLY is involved in tumor cell growth and metabolism. In some tumors, tumor cells express high levels of ACLY, enabling them to synthesize large amounts of fatty acids, CHOL and other biological molecules, thereby supporting the rapid proliferation and growth of tumor cells.19 Additionally, ACLY could play a role in the invasion and migration of malignant cells. For instance, ACLY overexpression can facilitate cell invasion and metastasis in colon cancer cells.20

PCa cells exhibit elevated levels of ACLY expression, enabling them to synthesize enough biomolecules such as fatty acids and CHOL to maintain cell proliferation and growth.21 Additionally, PCa cell invasion and metastasis are aided by ACLY. ACLY may serve as a therapeutic target for PCa.22 For example, some ACLY inhibitors have been developed that can effectively suppress PCa growth and metastasis.23 In PCa, ACLY activity is significantly enhanced, and it regulates fatty acid metabolism, which plays a significant role in the onset and progression of PCa. Thus, ACLY could be a good target for PCa therapy, opening brand-new therapeutic options.

Fatty acid synthase (FAS)

An essential enzyme called FAS plays a role in the production of fatty acids in the human body as part of the lipid metabolism process. It is primarily expressed in tissues such as the liver, adipose tissue, and mammary glands, and its function is to convert substrates such as acetyl-CoA and acetate into long-chain fatty acids, serving as an essential building block for lipid synthesis.24 Moreover, by creating lipid signaling molecules, FAS can control several physiological functions, such as cell division, proliferation, and death.

The expression level of FAS is significantly upregulated in PCa cells, possibly due to the high demand of PCa cells for fatty acids. High FAS expression is linked to PCa cell malignant features, including proliferation, invasion, metastasis, apoptosis resistance, and decreased tumor cell differentiation.25 These effects may be achieved through multiple pathways, including regulating cell signaling pathways, influencing the cell cycle and apoptosis, and increasing antioxidant capacity. The expression of FAS in PCa cells can be upregulated through multiple pathways. 1) androgen induction: androgen is a key hormone for the growth and development of PCa. By binding to AR, it can stimulate FAS expression. Overactivation of the AR signaling pathway can lead to upregulation of FAS expression, thus promoting the occurrence and development of PCa.26 2) AMP-activated protein kinase (AMPK) signaling pathway: AMPK is a key regulatory factor of cellular energy metabolism that can inhibit FAS expression. However, in PCa cells, due to abnormalities in the AMPK signaling pathway, FAS expression is upregulated, hence fostering PCa development and metastasis.27 3) Posttranscriptional modification: some posttranscriptional modification factors can directly or indirectly regulate the expression of FAS, thereby affecting the occurrence and development of PCa.28

Acetyl-CoA carboxylase (ACC)

Acetyl-CoA is converted into malonyl-CoA in the cell by the enzyme ACC, which catalyzes acyl transfer processes. ACC is crucial to fatty acid production and is involved in fatty acid metabolism. A crucial stage in the production of fatty acids, the reaction catalyzed by ACC, provides the acetyl group necessary to produce long-chain fatty acids.29 Recent research has found that abnormal expression of ACC is intimately associated with the development and incidence of different cancers.30 Preventing ACC expression can stop colon cancer cells from proliferating and invading.31

ACC is strongly connected to fatty acid production in PCa, which is a critical metabolic pathway for PCa cells due to their high demand for lipid metabolism. ACC expression is significantly increased in PCa tissues, highlighting its importance in the development of PCa. Recent research indicates that inhibiting ACC expression can reduce lipid synthesis in PCa cells, thereby decreasing the need for lipids and inhibiting PCa cell growth and metastasis.32 ACC also promotes PCa cell growth and metastasis through other mechanisms. Ueda et al.33 showed that ACC can regulate the cell cycle progression and apoptosis pathway of PCa cells, thereby promoting the growth and metastasis of PCa cells. In conclusion, ACC is a crucial component of PCa and may serve as a possible therapeutic target for the illness.

Fatty acid binding protein 5 (FABP5)

Fatty acid binding protein 5, commonly known as FABP5, is a member of the fatty acid binding protein family that is extensively expressed in a variety of tissues, including adipose tissue, skin, gut, liver, and mammary gland tissue. A vital component of cellular lipid metabolism, FABP5, controls the absorption, transportation, and metabolism of fatty acids.34 First, FABP5 is mainly involved in regulating endogenous fatty acid metabolism. FABP5 can bind and transport long-chain fatty acids to esterase on the cell membrane and endoplasmic reticulum, as well as engage in triglyceride synthesis, thereby participating in energy metabolism and storage. In addition, FABP5 can promote the oxidation of fatty acids, converting them into energy, and regulate energy metabolism by modulating mitochondrial respiratory chain function.

FABP5 was recently discovered as an essential regulator of lipid metabolism in PCa cells.35 In PCa tissues, FABP5 expression levels are linked to tumor malignancy and patient prognosis.36 FABP5 influences PCa cell proliferation, invasion, and metastasis by modulating the lipid metabolism pathway. FABP5 overexpression has been linked to PCa cell invasion and metastasis. FABP5 regulates not only the transport of fatty acids but also the synthesis and metabolism of inflammatory mediators. In addition, according to a previous study, FABP5 promotes the development of PCa by influencing the signal route of nuclear factor-kappa B (NF-κB).37 FABP5 may influence PCa cell proliferation and invasion by modulating NF-κB activation. Therefore, by regulating lipid metabolism and the NF-κB signaling pathway during PCa development, FABP5 has an impact on the proliferation, invasion, and metastasis of PCa cells.37 In terms of PCa therapy and prognosis assessment, FABP5 has emerged as a key molecular marker.

Stearoyl coenzyme A desaturase (SCD)

The fatty acid metabolism pathway is significantly regulated by the enzyme SCD. In the pathway of fatty acid metabolism, monounsaturated fatty acids are converted to polyunsaturated fatty acids through SCD. The latter is one of the essential nutrients in the human body because it is a key component of cell membranes and the precursor of some important signaling molecules. Additionally, polyunsaturated fatty acids can regulate the functions of metabolism and the immune system. Recent research has revealed that SCD is crucial for the development of various malignancies.38

SCD has been linked to the beginning and progression of PCa in recent studies. PCa cells exhibit high levels of lipid synthesis and metabolic activity, with high expression of SCD being a key factor in this process. SCD primarily promotes PCa proliferation and survival by regulating lipid metabolism and signaling pathways.39 Specifically, SCD promotes lipid and fatty acid synthesis, providing energy and metabolic substrates to support PCa growth and spread.40 In addition, SCD can regulate cell apoptosis and autophagy, inhibiting PCa cell death and promoting survival. Recent findings also suggest that SCD can activate signaling pathways that promote PCa metastasis and invasion.39 Therefore, SCD has become an important therapeutic target for PCa. Studies have shown that inhibition of SCD can effectively suppress PCa cell proliferation and survival while also enhancing PCa sensitivity to radiation therapy and chemotherapy.41 These findings imply that SCD is a potential therapeutic target for PCa.

Peroxisome proliferator-activated receptor gamma (PPARγ)

PPARγ is a nuclear receptor involved in regulating fatty acid metabolism and inflammation. Regarding lipid metabolism, PPARγ promotes fatty acid absorption and storage while inhibiting fatty acid oxidation.42 In addition, PPARγ is also involved in regulating physiological processes such as insulin sensitivity, CHOL metabolism, and lipid synthesis.43 PPARγ is well recognized as an important anticancer gene because it regulates cell proliferation, differentiation, and apoptosis by influencing the expression of several genes.

However, the precise mechanisms of PPARγ in PCa have not yet been fully elucidated. Several investigations have found that PPAR agonists reduce PCa cell growth and invasion while promoting cell death. Nonetheless, in some cases, PPARγ may also facilitate the development of PCa. Therefore, an in-depth understanding of the PPARγ mechanisms is critical for the development of innovative treatment methods. Olokpa et al.44,45 have shown that PPARγ agonists can hinder PCa development by impeding fatty acid synthesis and uptake in PCa cells. In addition, PPARγ agonists can also inhibit the development of PCa by interacting with other signaling pathways. For example, several studies have suggested that PPARγ can interact with various pathways to restrain the proliferation of PCa cells.44,45 In conclusion, although the precise mechanisms of PPARγ in PCa remain unclear, Hartley and Ahmad46 have revealed that PPARγ agonists can inhibit the development and progression of PCa via various pathways. Therefore, the development of PPARγ agonists may become a new strategy for treating PCa.

CHOL and PCa

CHOL is a lipid molecule that serves as a crucial component of cell membranes and various bioactive substances, as well as a crucial constituent of metabolites.47 Researchers conducted a study with 1314 patients who underwent radical prostatectomy for PCa as the primary subjects. The results indicated that a moderate decrease in CHOL induced by statin medications could reduce the risk of PCa recurrence. This suggests that medications and therapies affecting CHOL and CHOL metabolism may serve as novel treatment modalities and maintenance strategies for PCa.48 Additionally, a study was conducted on 69 patients who received local PCa treatment, analyzing samples of normal and tumor tissues from radical prostatectomy specimens. Researchers found a series of changes in PCa tissues compared to normal tissues, including increased CHOL intake, increased autonomous CHOL production by cells, and the accumulation of oxidative CHOL derivatives.49

PCa cells require CHOL as an important component of the cell membrane to support their rapid proliferation and growth. CHOL is also a substrate for other signaling and metabolic processes, including testosterone production, cell death, and immunological response.50 Notably, some PCa cell lines and clinical specimens have shown significantly elevated expression of FAS and CHOL efflux pumps compared to normal prostate cells, which may result in CHOL accumulation within PCa cells.51 In addition, PCa cells can upregulate CHOL synthesis and uptake via activation. On the other hand, disruption of CHOL metabolism may also exert detrimental effects on PCa progression. Studies have shown that abnormal CHOL uptake and metabolism can trigger increased inflammation and oxidative stress, thereby promoting PCa initiation and progression.52 Furthermore, some research suggests that reducing CHOL levels may inhibit PCa cell growth and migration and enhance their susceptibility to treatment. As a result, regulating CHOL metabolism might be a possible treatment method for PCa.53

Acyl coenzyme A-cholesterol acyltransferase (ACAT)

The membrane-bound enzyme ACAT is essential for the esterification of free CHOL into CHOL esters. Additionally, it catalyzes the reverse reaction to convert CHOL esters back to acyl-CoA. ACAT is extensively expressed in a variety of cell types, such as adipocytes, intestinal epithelial cells, and hepatocytes. ACAT is also involved in the metabolic conversion of CHOL esters.54 Recent research has revealed that ACAT significantly contributes to numerous cancer types.55

According to research, suppressing ACAT expression can lower CHOL levels, which decreases PCa cells’ ability to proliferate and invade.56 Lee et al.56 have emphasized the importance of ACAT in the expansion and invasion of PCa, highlighting its critical function in the progression of the illness. Therefore, ACAT could be a promising therapeutic target in the onset and progression of PCa. The development and invasion of PCa may be slowed by inhibiting ACAT, improving the prognosis for patients. To assess the effectiveness and safety of ACAT therapy for PCa, additional study is needed, as the present body of knowledge is still in its infancy.

3-hydroxy-3-methylglutaryl-coenzyme A synthase (HMGCS)

In the production of CHOL, HMGCS plays a crucial role.57 In the human body, HMGCS is mainly present in liver cells and intestinal cells. HMGCS also participates in the synthesis and modification of some biologically active substances, such as pigments, steroid hormones, and sterols. In addition to its role in the biosynthesis of cholesterol, HMGCS is also involved in several other biological processes. Recent research has shown the importance that HMGCS plays in certain malignancies, such as colorectal cancer.58 HMGCS is considered a potential therapeutic target.

Research has shown that PCa tissues have much higher levels of HMGCS expression, which is associated with improved tumor invasion and metastatic capacities. HMGCS participates in biological processes including CHOL metabolism and steroid hormone production, which have an impact on PCa development and metastasis.59 HMGCS is known to play a crucial role in CHOL metabolism and other important biological processes, further emphasizing its importance in PCa research. As the mechanism of HMGCS becomes better understood through further research, more therapeutic strategies targeting this enzyme may emerge in the future, bringing new hope for the treatment of these diseases.

3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR)

HMGCR is a crucial enzyme in the process that produces CHOL and is important for the body’s metabolism of cholesterol. In the route that produces cholesterol, HMGCR reduces the ketone body acetoacetyl-CoA to HMG-CoA, which is further catalyzed to cholesterol.60 This process is the rate-limiting step in CHOL synthesis and is a target for lowering CHOL levels. HMGCR inhibitors, such as statin drugs, have become one of the main drugs for treating hypercholesterolemia.61 In addition, HMGCR is also engaged in various metabolic processes, including the metabolism of homocysteine, isovaleric acid, and metabolism. Blocking HMGCR can successfully stop tumor cell proliferation and metastasis. For instance, in renal cancer, HMGCR inhibitors have been demonstrated to increase apoptosis and decrease cell growth.62

The occurrence and progression of PCa are associated with dysregulated CHOL metabolism, and HMGCR is an enzyme that is essential in the CHOL metabolism pathway. Orho-Melander et al.63 have shown the importance of HMGCR in the growth and metastasis of PCa cells. PCa cells’ ability to grow and spread is directly related to the degree of HMGCR expression, and PCa cells’ ability to proliferate and invade can be suppressed by HMGCR inhibitors.64 HMGCR is associated with PCa therapy in addition to its impact on PCa cell growth and metastasis. HMGCR inhibitors can increase the susceptibility of PCa cells to chemotherapy and radiation and boost therapeutic effectiveness.65 Moreover, HMGCR is closely related to the risk of PCa. A study indicated that high HMGCR expression is linked to a decreased survival rate in PCa patients, implying that HMGCR may serve as a prognostic biomarker for PCa.66

Phospholipids and PCa

Phospholipids are essential components of cell membranes and participate in many metabolic processes within cells, including the biosynthesis of liposomes, esters, and phosphatidylinositol (PI). In cancer development and progression, the significant role of phospholipid metabolism has been revealed. Albrecht67 has shown that cancer cells often require more phosphatidic acid synthase than normal cells, as they need more membranes to maintain their rapid proliferation. Changes in phospholipid metabolism are associated with cancer cell invasion and metastasis.67 Researchers obtained 49 surgical samples from patients undergoing radical prostatectomy to investigate the association between phospholipid metabolite concentrations in malignant prostate tissue and the pathological grade, proliferative status, and surgical staging of PCa. This study demonstrates that as the tumor progresses, high-grade PCa exhibits significantly elevated levels of phospholipid metabolites when compared to low-grade PCa.68

Abnormal phospholipid metabolism is one of the important mechanisms underlying cancer cell proliferation and metastasis in PCa. Abnormal phospholipid metabolism in PCa cells mainly manifests in two aspects: PI metabolism and sphingolipid metabolism. First, significant changes occur in PI metabolism in PCa. PI is a crucial phospholipid found in cell membranes and is involved in the control of several signaling pathways. Because of abnormal PI metabolism, the PI3K signaling pathway is overactivated in PCa cells, promoting cell proliferation and survival.69 These lipids are a type of phospholipid found in cell membranes and have significant biological functions that contribute to cell signaling and regulation. In PCa cells, abnormal sphingolipid metabolism is characterized by significantly increased activity of sphingomyelin synthase and sphingomyelinase, leading to enhanced cell proliferation and metastasis.70 In summary, phospholipid metabolism plays an important role in PCa, and abnormalities in both PI metabolism and sphingolipid metabolism can promote PCa cell proliferation and metastasis.

AMINO ACID METABOLISM AND PCA

Amino acids are essential substances with several biological functions. They serve as the building blocks of proteins and can participate in the synthesis of energy-metabolizing substances, as well as many important nitrogen-containing compounds, including hemoglobin, hormones, neurotransmitters, glutathione, nucleotides, coenzymes and nitric oxide (Figure 3a). Amino acids are also intimately related to carbohydrate and lipid metabolism. Through gluconeogenesis, amino acids can be transformed into glucose during the metabolism of carbohydrates. The amino acid skeleton can then join the glucose metabolism route and be fully oxidized. The intermediate products of glucose metabolism can be used to synthesize amino acids. All amino acids can be turned into fats in the human body through lipid metabolism. In addition, certain amino acids are also raw materials for synthesizing phospholipids (Figure 3b).

Figure 3.

Amino acid metabolic pathways and the relationship between amino acids produced and glucose and lipid metabolism. (a) The general situation of amino acid metabolism in the body. The amino acid metabolism library is formed through food digestion and absorption and the decomposition or synthesis of tissue cells in the body. The amino acid metabolism library is in dynamic balance and participates in decomposition, amino acid synthesis and metabolic transformation. (b) The amino acids participate in the body’s glucose and lipid metabolism and mutual transformation process. Glu: glucose; PPP: pentose phosphate pathway; PEP: phosphoenolpyruvate; Ala: alanine; Cys: cysteine; Ser: serine; Thr: threonine; Trp: tryptophan; Ile: isoleucine; Leu: leucine; Tyr: tyrosine; Lys: lysine; Phe: phenylalanine; Asp: aspartic acid; Asn: asparagine; Met: methionine; Val: valine; Arg: arginine; Gln: glutamine; His: histidine; TCA: tricarboxylic acid.

The role of amino acid metabolism in PCa is a topic of great concern. When PCa patients undergo ADT, various amino acid level alterations may occur, affecting the metabolism and biological processes of cancer cells. Specifically, there is an elevation in glutamine levels, prompting cancer cells to readjust their metabolism to adapt to androgen suppression, potentially impacting energy and nitrogen metabolism.71 Conversely, a decrease in arginine (Arg) levels influences polyamine synthesis and cell proliferation because of ADT.72 Furthermore, fluctuations in tryptophan (Trp) levels, linked to emotions and psychological states, may be related to patients’ mental well-being.73 Changes in methionine (Met) levels could also transpire, holding significance for protein synthesis and other crucial biological processes.74 As a result, treatment may influence Met metabolism, subsequently affecting protein synthesis and cellular function. Clinical research indicates that the levels of Arg and its metabolites play a significant role in predicting tumor markers, specifically prostate-specific antigen (PSA), in prostate biopsy results. This has been confirmed through tissue biopsies and liquid chromatography-tandem mass spectrometry analysis of plasma Arg levels in 78 PCa patients.75 Similar studies suggest a close correlation between indole-3-acetic acid, a breakdown product of Trp metabolism, and PSA levels as well as lymph node progression.76 In summary, amino acid metabolism in PCa holds clinical importance, particularly in the detection of amino acid metabolites. It serves as a valuable tool in the diagnosis, prognostic assessment, formulation of treatment strategies, and monitoring of treatment efficacy in PCa.77,78 Hence, through in-depth exploration of amino acid metabolism variations, more precise and effective approaches can be provided for the management and treatment of PCa patients (Table 2).

Table 2.

Summary of the molecular mechanisms of amino acid metabolism regulation in prostate cancer, involving enzymes, genes, and pathways

Amino acid	Model	Type	Effects	Mechanisms	Reference
Gln	22Rv1 and PC-3 cells ARCaPM mixed with CAFs xenograft mice	In vitro In vivo	↑The radio-sensitivity of PCa ↓Tumor volume	↓L-asparaginase and Gln	81
	PC-3, RM-1 and Myc-CaP cells RM-1 xenograft mice	In vitro In vivo	↑Fructose-6-phosphate amidotransferase-1 and protein glycosylation ↓Tumor growth, an improvement in tumor immune microenvironment	↑GFAT1 and IREα-Xbp1s pathway	82
Arg	PC-3, DU145, and LNCaP cells	In vitro	↓Autophagosome formation, autophagic flux, S6 kinase beta-1, 4E-binding protein 1, cell cycle progression and cell proliferation	↓EGFR downstream signaling pathways mTORC1 and mTORC2	85
Trp	LNCaP and PC-3 cells	In vitro	↑TPH-1, DOPA decarboxylase and monoamine oxidase A	↑5-HT	90
	PCa patients	In vivo	↑l-Trp, Kyn, anthranilate, isophenoxazine, glutaryl-CoA, (S)-3-hydroxybutanoyl-CoA, acetoacetyl-CoA, and acetyl-CoA ↓Indoxyl, indolelactate, and indole-3-ethanol	↑Trp metabolism along the Kyn pathway	92
Met	Using oral dosing of recombinant methioninase in cancer patients	In vivo	↓PSA, tumor growth and progression	↓Met	96

5-HT: 5-hydroxytryptamine; Arg: arginine; DOPA: l-3,4-dihydroxyphenylalanine; EGFR: epidermal growth factor receptor; GFAT1: glutamine-fructose-6-phosphate aminotransferase 1; Gln: glutamine; Kyn: kynurenine; Met: methionine; mTORC1: mammalian target of rapamycin complex 1; mTORC2: mammalian target of rapamycin complex 2; PSA: prostate-specific antigen; TPH-1: Trp hydroxylase-1; Trp: tryptophan; ↓: downregulation or inhibition; ↑: upregulation or activation

Gln and PCa

Gln, a nonessential amino acid, is synthesized mainly from Glu and methylamine transferase (MAT) and is widely involved in nitrogen and protein metabolism. It participates in three major metabolic pathways: the Gln-Glu cycle, urea cycle, and Gln biosynthesis.79 The Gln-Glu cycle involves the liver and kidneys converting ammonia in the blood into nontoxic urea using Gln to maintain nitrogen balance. The urea cycle is part of the Gln-Glu cycle, where amino acids are converted into urea in the liver and excreted from the body. Gln biosynthesis mainly occurs in the liver and muscles, where Gln produced by the muscles and liver is the main source of Gln supply for various tissues in the body. Furthermore, Gln has been demonstrated to have a significant function in tumors and cancer.80

Gln metabolism is a popular topic in PCa research. In fact, the level of Gln in prostate tissue is higher than that in normal tissue. Recent research has found that PCa cells show increased Gln metabolism, indicating that Gln metabolism plays a significant driving role in the initiation and progression of PCa.81 In PCa cells, the synthesis pathway of Gln is activated, and the level of Gln transporter protein is also increased. Studies have shown that the abnormal expression of the transcription factor c-Myc is associated with the activation of the Gln synthesis pathway in PCa cells.82 In addition, some studies have found that Gln is involved in the growth and spread of PCa by increasing DNA synthesis in PCa cells and promoting cell cycle progression.81 Therefore, linking abnormal Gln metabolism to the development of PCa is necessary. These recent discoveries provide fresh perspectives on PCa therapy and prevention.

Arg and PCa

Arg is a nonessential amino acid that is generated by methylation from Gln and ornithine transcarboxylase.83 In the human body, Arg plays various important physiological functions, such as protein synthesis in muscle, production of heparin, regulation of immune function, and involvement in energy metabolism. However, the expression levels of Arg are significantly increased in various cancers, notably in malignant cancers such melanoma, breast cancer, liver cancer, pancreatic cancer, and colorectal cancer, and Arg metabolism is related to tumor cell proliferation, invasion, and metastasis. Studies have revealed that Arg may activate the transcription factor signal transducer and activator of transcription 3 (STAT3), which is connected to the tumor grade and prognosis, and hence boost tumor cell proliferation and metastasis.84

Matos et al.72 have demonstrated that the pathways for Arg production and metabolism are abnormally active in PCa cells and are intimately associated with the occurrence and progression of PCa. Arg has the potential to be utilized in the diagnosis and treatment of PCa. Individuals with PSA levels between 4 ng ml⁻¹ and 10 ng ml⁻¹ can be diagnosed with PCa using Arg and its metabolites as a prognostic marker. These data may help predict the outcomes of prostate biopsies in PSA 4–10 ng ml⁻¹ individuals, offering novel strategies for PCa diagnosis.75 According to a variety of studies, Arg can prevent PCa cells from proliferating and invading by inducing apoptosis through its metabolites.85 However, current research is limited to laboratory studies, and further research is required to determine the potential value of Arg in PCa treatment. Moreover, the therapeutic efficacy of Arg may also be influenced by other factors, including the clinical stage of PCa, histological type, and tumor molecular markers. Therefore, when considering Arg as a potential treatment option for PCa, these variables must be considered. As research progresses, our understanding of the role of Arg in PCa development becomes more comprehensive, leading to the identification of more effective therapeutic approaches. Consequently, further studies are needed to comprehensively investigate the role of Arg in PCa treatment while considering individual variability and the potential influence of other variables.

Trp and PCa

Trp, an essential amino acid, serves as a component of proteins in the body and a precursor for the neurotransmitter serotonin and the hormone melatonin.86 Exogenous intake is the primary source of Trp synthesis in humans, which is then converted into serotonin or the precursor of vitamin B3, niacinamide, through multistep enzyme-catalyzed reactions.87 Trp metabolism is also associated with nitric oxide synthesis and modulation of gut microbiota. The significance of Trp in tumors has been thoroughly studied, and it has been discovered that Trp metabolic pathways play an important role in a variety of malignancies. Duitama et al.88 have reported that metabolic alterations in Trp pathways in cancer cells promote the effective acquisition of energy and biosynthetic materials for tumor cell survival.

A recent study revealed the critical involvement of Trp metabolism in the development and progression of PCa.89 The activity of Trp metabolic pathways is disrupted in PCa tissues compared to normal tissues, with significant upregulation of the expression levels of Try hydroxylase and aromatic L-amino acid decarboxylase in PCa tissues. These enzymes are involved in the metabolic pathway of Trp, where tryptophan hydroxylase (TPH) converts Trp to 5-hydroxytryptamine. These changes have been recognized as a significant contributor to aberrant Trp metabolism in PCa.90 In PCa cells, the expression levels of some key enzymes in the Trp metabolic pathway, such as tryptophan-2,3-dioxygenase2 (TDO2) and indoleamine 2,3-dioxygenase 1 (IDO1), are significantly increased, and the upregulation of these enzymes can generate intratumoral stimulating molecules in Trp metabolism, such as kynurenine (Kyn), which can directly or indirectly promote the development of PCa by activating tumor-associated immune responses.91,92 Moreover, this study found that blocking the Trp metabolic route successfully reduced PCa growth and invasion, indicating the potential of the Trp metabolic pathway as a viable therapeutic target. Furthermore, several studies have established the significance of the Trp metabolic pathway in PCa. The expression of the key enzyme TDO2 is considerably increased in PCa tissues, and this increase is strongly correlated with PCa malignancy.89 Another study revealed that inhibiting the major enzyme histone acetyltransferase in the Trp metabolic route might limit PCa cell proliferation and invasion, providing additional evidence for the importance of the Trp metabolic pathway in PCa development.93 Aberrant activation of the Trp metabolic pathway may be a vital driver of PCa development, making the inhibition of this pathway a promising therapeutic approach. However, more study is required to better understand the underlying processes of the Trp metabolic pathway in PCa and to create more effective treatment strategies.

Met and PCa

Met is a sulfur-containing amino acid that is necessary to produce proteins. Moreover, Met can be metabolized into various biologically active molecules. For example, it is a precursor for the biosynthesis of creatine, which is important for energy storage and transfer in muscles. Met also participates in biological processes such as protein methylation and antioxidant reactions. The role of Met has also been widely studied in many cancers. Met is essential for the initiation and spread of breast and stomach cancer. The biosynthesis of creatine is important for energy storage and transfer in muscles.94 Meanwhile, met deficiency may elevate the risk of developing PCa.95

The function of Met in different malignancies has been the subject of in-depth research. Han et al.96 have shown that patients with PCa have considerably lower blood levels of Met than healthy people. Dietary supplementation with Met may aid in reducing the risk of developing PCa.96 In summary, Met may have a multifaceted role in the development and advancement of PCa, and further research is needed to explore its mechanism of action.

DISCUSSION

Tumor metabolism refers to alterations in the synthesis and breakdown of intracellular metabolites during the development and progression of tumors. Tumor cells exhibit aberrant metabolic characteristics involving the metabolism of amino acids and lipids. This article focuses on the metabolic characteristics of PCa and analyzes and discusses them from two perspectives. The fatty acid synthesis pathway is significantly upregulated in PCa cells, with the PPARγ-mediated and ACC-regulated pathways being the most prominent. This increase is largely driven by alterations in fatty acid-related metabolic enzymes and binding proteins, including ACLY, FAS, ACC, SCD, and FABP5, among others. Furthermore, abnormal CHOL metabolism is closely linked to the growth and progression of PCa. CHOL has been demonstrated to enhance PCa cell growth and metastasis, with certain PCa cells displaying high levels of CHOL production and overexpression of CHOL transport proteins, allowing them to absorb more CHOL from the circulation. CHOL, as a signaling molecule, also regulates the development and spread of PCa cells. This process is similarly influenced by various CHOL-related regulatory enzymes. This article mainly discusses changes in the amino acid metabolism pathways, including Gln, Arg, Trp, and Met, and their effects on PCa amino acid metabolism. These findings imply that regulating amino acid metabolism may aid in the prevention of PCa cell growth and spread, hence assisting in the treatment and prevention of PCa. These metabolic characteristics provide necessary nutrients and energy for the growth and survival of PCa cells. Therefore, metabolic pathways may be potential therapeutic targets in PCa treatment, and related research may provide an important theoretical basis for developing new methods to treat PCa.

Through a comprehensive understanding of these two metabolic pathways, effective approaches for formulating PCa treatment plans can be developed based on the following five aspects (Figure 4). 1) Targeted therapy: exploring novel therapeutic approaches for PCa by intervening in lipid metabolism and amino acid metabolism. This includes the development of metabolic inhibitors or activators targeting specific enzymes or signaling pathways, such as inhibitors targeting ACLY, ACC, FAS, FABP5, HMGCS, and ACAT, as well as activators of PPARγ, to inhibit tumor cell growth and survival. 2) Combination therapy: combining lipid and amino acid metabolic targeted therapy with existing PCa treatment methods for potential synergistic effects. This may involve combining radiation therapy, immunotherapy, or the use of chemotherapy drugs. For example, inhibitors targeting SCD and HMGCR can effectively suppress PCa cell proliferation and survival and enhance PCa sensitivity to radiation therapy and chemotherapy, thereby improving treatment efficacy and prognosis. 3) Combination drug therapy: simultaneous use of anti-Arg drugs and polyamine synthesis inhibitors, may produce a synergistic effect in PCa treatment97. 4) Dietary intervention: further research on the potential of diet in regulating lipid and amino acid metabolism. This may include restricting high-fat diets, adjusting dietary composition to increase healthy fat intake, and modulating amino acid supply through dietary strategies. Insulin signaling pathways and the IGF pathway are associated with PCa growth. Dietary interventions that regulate insulin and IGF signaling may help control PCa. Additionally, dietary supplementation with Met may help reduce the risk of PCa occurrence98. 5) Regulation of the tumor microenvironment: treatment methods targeting factors such as cells, cytokines, extracellular matrix, and blood vessels in the PCa microenvironment aim to alter the growth environment of PCa, inhibiting its growth and metastasis. Modulating Trp metabolism, particularly by inhibiting the formation of the Trp metabolite Kyn, can regulate the tumor microenvironment, enhance immune responses, and suppress PCa progression. This article aims to provide a comprehensive review of PCa-related research, offering a theoretical basis for the development of new treatment methods and further investigations.

Figure 4.

Potential therapeutic strategies for PCa in lipid and amino acid metabolism. Targeted therapy: interventions in lipid metabolism and amino acid metabolism to target PCa therapies. Regulation of the tumor microenvironment: it can regulate the tumor microenvironment, enhance the immune response, and inhibit the progression of PCa. Dietary intervention: dietary strategies were used to control PCa. Combination therapy: potential therapy for targeting lipid and amino acid metabolism in combination with existing treatments for PCa. Combination drug therapy: the combination of anti-Arg drugs and polyamine synthesis inhibitors is used to target PCa. PCa: prostate cancer; AMPK: AMP-activated protein kinase; NF-κB: nuclear factor-kappa B; ACLY: ATP citrate lyase; ACC: acetyl-CoA carboxylase; FAS: fatty acid synthase; FABP5: fatty acid binding protein 5; HMGCS: 3-hydroxy-3-methylglutaryl-coenzyme A synthase; ACAT: acyl coenzyme A-cholesterol acyltransferase; SCD: stearoyl coenzyme A desaturase; HMGCR: 3-hydroxy-3-methylglutaryl-coenzyme A reductase; IDO: indoleamine-2,3-dioxygenase; TDO: tryptophan-2,3-dioxygenase; Trp: tryptophan; Kyn: kynurenine; L-Met: L-Methionine; IGF: insulin-like growth factor.

AUTHOR CONTRIBUTIONS

LC and JLZ conceived the structure of the manuscript and revised the manuscript. LC and YSW drafted the initial manuscript. YXX made the figures and tables. All authors read and approved the final manuscript.

COMPETING INTERESTS

All authors declare no competing interests.