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. 2023 Dec 11;15(24):5797. doi: 10.3390/cancers15245797

Table 1.

No Synthesis Metabolites in ccRCC.

NO Parameters (References) Biological Systems Results Conclusions
Calcium-dependent and calcium-independent NO synthetase [42] Human kidney/RCC, proximal tubular cell lines HN4, HN51. Calcium-dependent NOS activity, identified in all the samples studied, was downregulated in RCC compared to non-malignant renal tissues studied; calcium-independent NOS activity was inconsistently expressed in the renal tissue. NO exerted cytostatic effects on cultured renal cells.
NOS1, NOS2, NOS3 [43] Non-neoplastic renal tissues and RCC In non-neoplastic tissues, NOS3 immunoreactivity was increased and NOS2 was reduced compared to RCC. The NOS expression was correlated with tumour size and a poor prognosis. NOS3 as a predictive factor in RCC
NOS, sGC, nitrotirosine [44] Normal and tumoural renal tissue (benign and malignant tumours). NOS1 is downregulated in malignant tissues and associated with the tumour grade; sGC is present in all renal tumours; nitrotyrosine is present in normal renal parenchyma and tumour tissues. Autocrine signalling of NO is similar in normal and non-malignant renal tissues and altered in malignant tissues
Nitrites [45] Serum (apparently healthy women diagnosed with RCC) Elevated serum level in patients with RCC Elevated serum nitrite levels are associated with a low risk of renal cancer.
ASS1, ASL, Arg2 [46,47] RCC tissue samples and control mRNA and ASS1, ASL, Arg2 activity are reduced in RCC vs. normal kidney
Altered urea cycle-metabolic pathway in RCC.
Attenuation of the cytotoxic effects of NO.
ASS1, ASL, Arg2 -metabolic suppressors in RCC.
NOSi-ARN [31] RCC and control tissue samples mRNA and iNOS protein present in tumour thrombi in patients with RCC and in A498 and A704 cells under hypoxic conditions. It mediates the formation of tumour thrombi and hypoxic adaptation.
Arg2, ASS1 [46,48] Normal and malignant renal cell lines The expression of enzymes in the urea cycle is downregulated in RCC compared to the control. Deficiency of enzymes in the urea cycle disrupts polyamine synthesis, conservation of pyridoxal phosphate, arginine auxotrophy, infiltration of cytotoxic T cells in the tumour tissue, and immunosuppression in the tumour microenvironment. Arg2 and ASS1 are potential metabolic suppressors of renal tumourigenesis.
ASS1, ADI (E.C.3.5.3.6) [35] Biopsy samples, animal models, cell lines. Low or undetectable ASS1 in RCC, present in normal proximal tubule epithelium. Exogenous ADI (arginine deiminase) determines antiproliferative and antiangiogenic effects in vivo on RENCA tumour cells and extends the survival of tumour-bearing mice. Arginine deprivation via ADI—an antitumour strategy in RCC
Spermine, spermidine [49] Normal and malignant human renal tissue Spermidine levels and spermidine/spermine ratio increase; normal tissue < differentiated RCC < poorly differentiated RCC. The other polyamines do not show differences between normal tissues, tumours, and metastases. Polyamines—biochemical markers for the malignancy of RCC
Diamine, spermidine, spermine [50] Tissue, urine, blood Elevated levels are correlated with the progression of RCC Polyamines—tumour markers in RCC
Agmatinase (E. C.) [51] Normal and malignant renal tissue The expression and mRNA of agmatinase are decreased in RCC compared to benign renal tumours. Accumulated agmatine stimulates NOS3 and NOS2, leading to NO synthesis. Reduced agmatinase increases the cytotoxic activity of NO in RCC
RNS, NO2 [52] Cell cultures JS-K, a NO donor, stimulates the increase in ROS (Reactive Oxygen Species) and RNS (Reactive Nitrogen Species), the reduction in GSH/GSSG (glutathione redox status), the increase in pro-apoptotic proteins (Bak, Bax), and the reduction in anti-apoptotic proteins (Bcl-2) in RCC (Renal Cell Carcinoma). JS-K induces apoptosis in cancer cells by modulating the production and signalling of NO, MAPK (Mitogen-Activated Protein Kinase), the ubiquitin–proteasome pathway, and the β-catenin/T-cell factor (TCF) signalling pathway NO released by JS-K induces apoptosis in renal carcinoma cells by increasing the levels of ROS/RNS and induces chemosensitivity of tumour cells to doxorubicin
NOS, cGMP [53] Experimental and human tumours. The NOS enzymes are overexpressed in tumour tissues. NO metabolites correlate with angiogenesis and tumour aggressiveness.
Dietary nitrite, nitrate intake [54] Evaluation of nitrates and nitrites in food sources (41 articles, 13 types of cancer). Nitrates from plant sources and nitrates in general do not affect the development of renal cancer. Nitrites from processed meat are associated with an increased risk of renal cancer < pancreatic cancer < thyroid cancer, stomach cancer, glioma, and others. The nitrites/nitrates intake has specific effects on the type and site-specific risk of cancer
Phytonutrients [55,56,57,58,59,60] Epidemiological studies on the role of dietary factors. Phytonutrients play an essential role in cancer prevention. Dietary sources of nitrites and nitrates have a role in immunity and vascular function. Dietary sources of nitrites include vegetables, fruits, and processed meat. Vitamin C inhibits endogenous nitrosation.
Red and processed meat [61] Meta-analysis (12 case-control studies, 16 cohorts) No statistically significant data were obtained between the consumption of red and processed meat, individual variables (BMI, smoking, total energy intake), and the development of renal cancer. An independent relationship between meat consumption and the risk of renal cancer was not evident.
Red and processed meat [62] Meta−analysis (23 eligible publications) on the association and impact of red meat consumption on RCC Positive relationship between consumption of beef, salami, ham, bacon, sausages, hamburgers, and renal cancer. Statistically significant positive association between red meat consumption and RCC
Dietary factors [63,64] Report on 22 meta−analyses (566 publications). No suggestive or convincing evidence between the consumption of foods, beverages, alcohol, macronutrients, micronutrients, and the incidence of RCC The intake of vegetables and vitamin C is associated with the risk of RCC
Serum NO2−, NO3 [65] RCC patients and control patients No significant differences between patients and controls.
Variations depending on the tumour grade.
NO exerts immunoregulatory effects in RCC
Arginase 2 [66] Murin renal cell lines, normal and neoplastic. Arginase 2 rapidly metabolizes L-arginine, suppresses tumour growth, and reduces the expression of CD3zeta. Arginase 2 modulates the function of T cells, depleting arginine.
Arginase 2 [67] Peripheral blood of metastatic RCC and control patients Myeloid suppressor cells producing arginase present in patients with metastatic ccRCC Arginase 2 regulates the availability of arginine.
Arginase 2 [7] Arginase 2 supports the growth of ccRCC
BCAA, BCAT, ASS1 [1,21,68,69,70] Cultured primary and metastatic renal cancer cells (omic study) Transcriptionally suppressed BCAA catabolism, overexpressed BCAT, urea cycle, glutathione, cysteine/methionine, arginine, glutamine, tryptophan, reactivated polyamines in ccRCC show metabolic flexibility during tumour progression and offer invasive potential. Altered metabolic advantage for cancer cell survival
SIRTs [34,36,71,72,73] ccRCC cells, cell lines, genetic models, pharmacological models, omic studies, computational SIRTs-1,3,6,7 maintain renal homeostasis. SIRT1 regulates NOSe in glomerular cells. NO regulates the stability of the SIRT3/TRAP1 complex.
SIRT3 has dual effects on tumour growth.
SIRT3 has antioxidant and anti-inflammatory effects in kidney disease.
SIRT4 inhibits glutamine metabolism
Activating SIRTs before tumour initiation is a preventive strategy. NO/SIRT3 regulates mitochondrial biogenesis in ccRCC and cell sensitivity to antitumour therapy.