Activation of p38/HSP27 pathway counters melatonin-induced inhibitory effect on proliferation of human gastric cancer cells

Overexpression of heat shock protein 27 (HSP27) in gastric cancer is correlated with poor clinical prognosis. Melatonin, an endogenous hormone, shows promise in gastric cancer therapy. However, there is limited study on the biological activity of HSP27 in response to melatonin treatment. In this study, we show an anti-proliferative action of melatonin on human gastric cancer cell lines BGC-823 and MGC-803. Biochemically, the inhibitory effect of melatonin is accompanied by the upregulation of HSP27 phosphorylation level. Transfection of gastric cancer cells with HSP27-specific siRNA effectively reduces HSP27 phosphorylation and potentiated melatonin-induced inhibitory effect on cell proliferation. The reduction of cyclin D1 in melatonin-treated cells is also aggravated by HSP27 depletion. Moreover, melatonin stimulation increases p38 phosphorylation. Pretreatment with p38 inhibitor SB203580 not only remarkably suppresses melatonin-induced HSP27 phosphorylation, but also augment the inhibitory effect of melatonin on cyclin D1 expression as well as cell proliferation. Taken together, our study indicates the protective pathway of p38/HSP27 against melatonin-induced inhibitory effect on gastric cancer cell proliferation, suggesting that combined with p38/HSP27 pathway inhibitor, the therapeutic efficacy of melatonin on gastric cancer may be improved.