Melatonin inhibits lipid accumulation to repress prostate cancer progression by mediating the epigenetic modification of CES1

Abstract

Background Androgen deprivation therapy (ADT) is the main clinical treatment for patients with advanced prostate cancer (PCa). However, PCa eventually progresses to castration‐resistant prostate cancer (CRPC), largely because of androgen receptor variation and increased intratumoral androgen synthesis. Several studies have reported that one abnormal lipid accumulation is significantly related to the development of PCa. Melatonin (MLT) is a functionally pleiotropic indoleamine molecule and a key regulator of energy metabolism. The aim of our study is finding the links between CRPC and MLT and providing the basis for MLT treatment for CRPC. Methods We used animal CRPC models with a circadian rhythm disorder, and PCa cell lines to assess the role of melatonin in PCa. Results We demonstrated that MLT treatment inhibited tumor growth and reversed enzalutamide resistance in animal CRPC models with a circadian rhythm disorder. A systematic review and meta‐analysis demonstrated that MLT is positively associated with an increased risk of developing advanced PCa. Restoration of carboxylesterase 1 (CES1) expression by MLT treatment significantly reduced lipid droplet (LD) accumulation, thereby inducing apoptosis by increasing endoplasmic reticulum stress, reducing de novo intratumoral androgen synthesis, repressing CRPC progression and reversing the resistance to new endocrine therapy. Mechanistic investigations demonstrated that MLT regulates the epigenetic modification of CES1. Ces1‐knockout (Ces −/− ) mice verified the important role of endogenous Ces1 in PCa. Conclusions Our findings provide novel preclinical and clinical information about the role of melatonin in advanced PCa and characterize the importance of enzalutamide combined with MLT administration as a therapy for advanced PCa.

Melatonin and Pathological Cell Interactions: Mitochondrial Glucose Processing in Cancer Cells

“…Therefore, it seems possible that every cell harbors MT1 and/or MT2 receptors. Many of the functions of melatonin in modulating oncogenic transformation are mediated by signaling events that follow the binding of melatonin to its membrane receptors [2,7,130,131].…”

“…Melatonin has long been known to be an endogenously produced anti-cancer agent [1][2][3][4][5][6][7][8]. This action has been confirmed for multiple tumor types [9][10][11][12][13][14] and in both in vitro [15][16][17][18] and in vivo [19][20][21][22][23][24][25][26] studies.…”

Melatonin—A New Prospect in Prostate and Breast Cancer Management

“…Therefore, it is urgent to find new cost-effective therapeutic alternatives with fewer side effects. A mechanistic study revealed that melatonin reduces PC progression to CRPC by decreasing lipid accumulation and activity in PC cells via upregulating the lipid metabolism-related gene carboxylesterase (CES) 1 in PC cells [27].…”

Microenvironmental Factors Modulating Tumor Lipid Metabolism: Paving the Way to Better Antitumoral Therapy

“…Excessive lipids are then usually stored in lipid droplets (LDs) as neutral lipids (mainly triglycerides (TGs) and cholesterol esters (CEs)). Indeed, LD accumulation is widely observed in many human malignancies such as prostate cancer ( 43 ), glioblastoma ( 44 ) and ovarian cancer ( 45 ). It’s increasingly considered as an emerging hallmark of cancer aggressiveness, especially in tumor cells exposed to nutrient deprivation and hypoxia ( 46 , 47 ).…”