Melatonin impedes prostate cancer metastasis by suppressing MMP‐13 expression

• Published in: Journal of cellular physiology 2021-05, Vol.236 (5), p.3979-3990
• Main Authors: Wang, Shih‐Wei, Tai, Huai‐Ching, Tang, Chih‐Hsin, Lin, Liang‐Wei, Lin, Tien‐Huang, Chang, An‐Chen, Chen, Po‐Chun, Chen, Yi‐Hsuan, Wang, Po‐Chuan, Lai, Yu‐Wei, Chen, Shiou‐Sheng
• Format: Article
• Language: English
• Subjects: Animals; Anticancer properties; Antitumor activity; Cell Death - drug effects; Cell Line, Tumor; Cell Movement - drug effects; Cell Survival - drug effects; Down-Regulation - drug effects; Gene expression; Growth rate; Human tissues; Humans; Invasiveness; Male; Matrix Metalloproteinase 13 - metabolism; Matrix metalloproteinases; Melatonin; Melatonin - pharmacology; Metalloproteinase; Metastases; Metastasis; Mice; Mice, SCID; MMP‐13; Models, Biological; MT1 receptor; Neoplasm Invasiveness; Neoplasm Metastasis; Organs; p38 Mitogen-Activated Protein Kinases - metabolism; Phospholipase C; Prostate cancer; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - pathology; Proto-Oncogene Proteins c-jun - metabolism; Receptors, Melatonin - metabolism; Sleep; Type C Phospholipases - metabolism
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.30150

Prostate cancer has high metastatic potential. Men with higher urinary levels of the sleep hormone melatonin are much less likely to develop advanced prostate cancer compared with men with lower levels of melatonin. Melatonin has shown anticancer activity in experimental investigations. Nevertheless, the therapeutic effect of melatonin in metastatic prostate cancer has largely remained a mystery. Analyses of Gene Expression Omnibus data and human tissue samples indicated that levels of matrix metallopeptidase 13 (MMP‐13) expression are higher in prostate cancer patients than in healthy cancer‐free individuals. Mechanistic investigations revealed that melatonin inhibits MMP‐13 expression and the migratory and invasive capacities of prostate cancer cells via the MT1 receptor and the phospholipase C, p38, and c‐Jun signaling cascades. Importantly, tumor growth rate and metastasis to distant organs were suppressed by melatonin in an orthotopic prostate cancer model. This is the first demonstration showing that melatonin impedes metastasis of prostate cancer by suppressing MMP‐13 expression in both in vitro and in vivo models. Thus, melatonin is promising in the management of prostate cancer metastasis and deserves to undergo clinical investigations. Melatonin acts on the MT1 receptor and inhibits phospholipase C (PLC) and p38 signal cascades, subsequently suppresses matrix metallopeptidase 13 (MMP‐13) expression through the c‐Jun‐dependent pathway, leading to the reduction of prostate cancer metastasis. This is the first indication that melatonin impedes metastasis via the targeting of MMP‐13 in prostate cancer cells, based on evidence from basic and clinical studies.