Melatonin Promotes Apoptosis of Colorectal Cancer Cells via Superoxide-mediated ER Stress by Inhibiting Cellular Prion Protein Expression

Background/Aim: Melatonin, an endogenously secreted indoleamine hormone that is produced in the pineal gland, is known to possess antitumor effect via various mechanisms including induction of apoptosis and pro-oxidant effects in various cancer cells, including colorectal cancer (CRC). In our study, we hypothesized that melatonin enhances the anticancer effects via suppression of PrPC and PINK1 levels, thereby increasing superoxide production. Materials and Methods: To investigate the antitumor effects of melatonin in CRC cells, assessing its effects on mitochondrial dysfunction, production of superoxide, induction of endoplasmic reticulum stress, and cellular apoptosis were assessed. Results: Melatonin was found to decrease the expression of PrPC and PINK1, and increase superoxide accumulation in the mitochondria. In addition, PrPC-knockdown potentiated the effects of melatonin resulting further in significantly reduced expression of PINK1 and increased superoxide production in CRC. siPRNP-transfected CRC cells treated with melatonin increased the production of intracellular superoxide and induced endoplasmic reticulum stress associated protein, and apoptosis. Conclusion: Melatonin induces mitochondria-mediated cellular apoptosis in CRC cancer cells via a PrPC-dependent pathway. PrPC knockdown combined with melatonin amplifies the effects of melatonin, suggesting a novel therapeutic strategy in targeting CRC cells.