Table 1.

Summary of genomic–metabolomic integration studies for PCa within the last decade (2011–2021) ^1,2.

Reference	Experimental Condition	Sample/ n Samples	Analytical Tool for Metabolites	Altered Metabolites (+/−)	Dysregulated Metabolic Pathways	Main Findings
Hsu et al., 2021 [144]	Arginine starvation	Cell lines: CWR22Rv1, PC3, MDA-MB-231	LC-MS Seahorse flux analysis	Arginine metabolites (−) α-ketoglutarate (−)	Oxidative phosphorylation DNA repair pathway Type I interferon response	Deficiency in arginine synthesis (defects in PCa), performed as arginine starvation resulted in cell death via epigenetic silencing and metabolite depletion. cGAS-STING activation contributed to cell death.
Cai et al., 2020 [217]	Citrate synthase (CS) down- regulation	71 = adenocarcinoma 2 = leiomyo-sarcoma 1 = hyperplasia 6 = normal	UPHPLC-MS/MS Seahorse assay	Glyceraldehyde 3-phosphate (−) Citrate (−)	Lipid metabolism Mitochondrial function	CS expression: PCa > normal prostate. Decreased CS expression resulted in inhibited PCa proliferation, colony formation, migration, invasion, cell cycle in vitro, and low tumor growth in vivo. CS downregulation lowers lipid metabolism and mitochondrial function.
Kim et al., 2020 [145]	Withaferin (WA) treatment	22Rv1 LNCaP, 22Rv1 (validation) Hi-MYC	Fluorometric assay	ATP citrase lyase, acetyl-coA carboxylase 1, fatty acid synthase, carnitine palmitoyltransferase (−)	Fatty acid synthesis	WA treatment in all cell lines downregulated mRNA and protein levels of key fatty acid synthesis enzymes. Suppression of a acetyl-coA carboxylase, expression of fatty acid synthase, and PCa cell survival from WA treatment → expression of c-MYC, not AKT.
Adams et al., 2018 [146]	Metabolite-PCa causality	24,925 = GWAS metabolites 44,825 = GWAS PCa 27,904 control	Data mining and statistical analysis, no experimental tool	Lipids and lipoproteins Fatty acids and ratios Amino acids Fluids 35 metabolites association w/ PCa, 14 has no causality	Lipid metabolism Fatty acid metabolism Amino acid metabolism	35 metabolites were associated w/ PCa, and 14 of those were found not to have causality w/ PCa progression.
Khodayari-Moez et al., 2018 [136]	AKT and MYC dysregulation	60 = human PCa samples 16 = normal prostate	Data analysis, no experimental tool	Metabolites related to dysregulated metabolic pathways	D-glutamine and D-glutamate metabolism Fatty acid biosynthesis Fructose and mannose Metabolism Nitrogen metabolism Pyrimidine metabolism	Dysregulation of AKT1 and MYC alters non-glucose-mediated pathways and their downstream targets. MYC is one of the leading oncogenes in PCa development.
Heger et al., 2016 [128]	Sarcosine dehydro- genase (SDH) supplementation	PC3, LNCaP PCa murine xenograft (validation)	IEC	Glycine, serine, sarcosine (+) dimethylglycine and glycine-N-methyltransferase (slight +)	Sarcosine metabolism	SDH supplementation significantly increased levels of glycine, serine, and sarcosine, but slight increase in dimethylglycine and glycine-N-methyltransferase levels. PC-3 → 25, LNCaP → 32, overlapping → 18 differentially expressed genes.
Liu et al., 2015 [137]	Gene-metabolite association	16 = benign 12 = PCa 14 = metasta- sized	Mathematical, no experimental tool, second-hand LC/GC-MS from Sreekumar et al.	1353 genes 1489 metabolites	Non-applicable	Directed random walk global gene-metabolite graph (DRW-GM) = from integrated matched gene and matched metabolomic profiles →accurate evaluation of gene importance and pathway activities in PCa. Use of method in three independent datasets → accurate evaluation of risk pathways.
Shafi et al., 2015 [186]	Androgen receptor variant 7 (AR-V7)	LNCaP	Seahorse assay LC-MS	Glucose/fructose (−) 3-phosphoglycerate, 2-phosphoglycerate (−) Pyruvate (+) Citrate (−) α-ketoglutarate (+) Malate (−) Oxaloacetate (+) Glutamine (+) Citrate (−)	Glycolysis via extracellular acidification rate (ECAR) Glutamine metabolism via reductive carboxylation Tricarboxylic acid (TCA) cycle Glutaminolysis	AR-V7 stimulated growth, migration, and glycolysis measured by ECAR (extracellular acidification rate) similar to AR. AR → increase citrate, AR-V7 → reduce citrate mirroring metabolic shifts (castration-resistant PCa). AR-V7 is highly dependent on glutaminolysis and reductive carboxylation → produce metabolites consumed by TCA cycle.
Gilbert et al., 2014 [218]	SNPs of vitamin D-PCa association	1275 = PCa 2062 = healthy controls	MS	25-hydroxyvitamin-D (25(OH)D) 1,25-dihydroxyvitamin, (1,25(OH)2D)	25(OH)D synthesis 25(OH)D metabolism	Vitamin D-binding protein SNPs were associated with prostate cancer. Low 25(OH)D metabolism score was associated with high grade.
Zecchini et al., 2014 [219]	Beta-arrestin 1 (ARB1)	C4-2 786-O	1,2-13C2 glucose assay GC-MS	Succinate dehydrogenase Fumarate hydratase	Oxidative phosphorylation Aerobic glycolysis	ARB1 contributes to PCa metabolic shift via regulation of hypoxia-inducible factor 1A (HIF1A) transcription through regulation of succinate dehydrogenase and fumarate hydratase in normoxic conditions. ARB1 was directly linked in PCa as a promoter by altering metabolic pathways. Survival of PCa cells in harsh conditions due to ARB1.
Hong et al., 2013 [220]	Metabolic quantitative trait loci (mQTLs) via genome-wide association study (GWAS)	214 = PCa 188 = control 489 = PCa (replication)	UPLC-MS w/ XCMS	Caprolactam Glycerolphosphocholine 2,6-dimethylheptanoylcarnitine Glycerolphosphocholine Bilirubin C9H14Ona Glycerophospho-N-palmitoyl ethanolamine Stearoylcarnitine Glycochenodeoxycholic acid 3-glucuronide	Fatty acid β-oxidation via acyl-CoA dehydrogenase	Seven genes (PYROXD2, FADS1, PON1, CYP4F2, UGT1A8, ACADL, and LIPC) and their variants contributed significantly to trait variance for one or more metabolites. Enrichment of 6 genes was associated w/ increased ACAD activity. mQTL SNPs and mQTL-harboring genes over-represented in GWAS → implications in PCa.
Poisson et al., 2012 [221]	Gene expression mapping	402 = original 488 = replication	Statistical and mathematical, no experimental tool	Non-applicable	Non-applicable	Convert gene information to p-value weight via 4 enrichment tests and 4 weight functions. Used p weights on PCa metabolomic dataset. Disjoint pathways → higher capability to differentiate metabolites than enriched pathways.
Lu et al., 2011 [222]	Single-minded homolog 2 (SIM2) expression	PC3 LNCaP VCaP DU145	LC-MS-MS	38 dysregulated metabolites	PTEN signaling PI3K/AKT signaling Toll-like receptor signaling	Lenti-shRNA in PC3 → downregulates SIM2 gene and protein → affects key signaling and metabolic pathways.
Massie et al., 2011 [223]	AR regulatory effects	LNCaP	NMR 1,2-13C2 glucose assay GC-MS	Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2)	Glycolysis via activating 5’ AMP-activated protein kinase (AMPK)- phosphofructokinase (PFK) signaling	AR regulates aerobic glycolysis and anabolism in PCa. CAMKK2, a direct AR target gene, regulates downstream metabolic processes. CAMKK2 is important in androgen-dependent and castration-resistant PCa.

¹ The list is non-exhaustive, tabulated as of the writing of this review article. ² Total of 91 queries trimmed down to 14 integrated genomic-metabolomic PCa studies.