Table 1.

Biological Pathways Linking CRDs and Prostate Cancer. The table provides a summary of pathways in which CRDs contribute to prostate cancer incidence and outcomes. The upward arrow refers to pathways, genes, or proteins that are upregulated, while the downward arrow refers to downregulated pathways, genes, or proteins.

CRD-related Pathways		Effect on Prostate Cancer	Therapeutic Targets
Circadian Gene Variants	Per 1, Per 2, and Clock ↓ and Bmal1 ↑ [124]	Increased risk of Pca [124]	Melatonin ↑ Per 2 and Clock and ↓ Bmal1 levels [125]
	Per 1-3, CSNK1E, Cry 1-2, BMAL1, CLOCK and NPAS2 SNPs [29]	Greater risk of aggressive Pca [29]	Overexpression of Per 1 and Per 2 induces growth inhibition [124]
	Per 3 pathway [31]	Regulation of PCSCs [31]	CRY1 levels promote DNA repair and cancer survival [30]
			Per1 decreased AR-related genes in the presence of DHT [126]
Stress	Glucocorticoids ↑ CLU and LEDG/p75 [127]	Pca therapy resistance [127]	RU-486 and cyproterone acetate revert docetaxel resistance [128]
	↑ GR transcript expression following anti- androgen therapy [129]	Tumor progression in mCRPC [129]	SGK1 antagonist blocks AR-mediated growth [130]
			SGRMs ↓ GR transcriptional activity and ↓ GR-mediated tumor cell viability post-AR blockade [131]
	GR upregulation [132]	Bypass AR blockade [132]
Obesity	↑ Leptin [34]	Migration [34]	MAPK and PI3K inhibits migration of Pca cells in the presence of leptin [34]
	NPAS2, Per 1, Per 3, Cry 2, and CSNK1E [133]	Altered IGF-1 and androgen [133]
Melatonin Inhibition	↓ 6-STM serum levels [134]	Increase risk for advanced Pca [134]	Melatonin inhibits Pca cell proliferation, ↓ AR signaling and ↓ p27 pathway [135]
	↓ melatonin: cortisol ratio and PSA levels [136]	Increased risk for primary and advanced Pca [136]	Melatonin inhibits glycolysis and the pentose phosphate pathway [137]