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Melatonin sensitizes human hepatoma cells to endoplasmic reticulum stress–induced apoptosis
Author(s) -
Zha Lixia,
Fan Lulu,
Sun Guoping,
Wang Hua,
Ma Tai,
Zhong Fei,
Wei Wei
Publication year - 2012
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/j.1600-079x.2011.00946.x
Subject(s) - apoptosis , endoplasmic reticulum , tunicamycin , unfolded protein response , chop , biology , endocrinology , medicine , programmed cell death , cancer research , microbiology and biotechnology , chemistry , biochemistry
Endoplasmic reticulum stress–mediated cell apoptosis is implicated in the development of cancer. Melatonin induces apoptosis in hepatocellular carcinoma (HCC) in experimental studies, but the effects of melatonin on endoplasmic reticulum (ER) stress–induced apoptosis in HCC have not been tested. Differences in ER stress–induced apoptosis in human hepatoma cells and normal human hepatocyte were investigated by exposure to tunicamycin (ER stress inducer). Significant differences were observed in the rate of apoptosis between HepG2 cells (hepatoma cells) and HL‐7702 cells (normal human hepatocyte cells). The expression of cyclooxygenase‐2 (COX‐2) was increased in HepG2 cells but not in HL‐7702 cells. Furthermore, down‐regulation of COX‐2 expression using the COX‐2 inhibitor, celecoxib, increased tunicamycin‐induced apoptosis concomitant with the up‐regulation of pro‐apoptotic transcription factor CHOP (GADD153) and down‐regulation of B‐cell lymphoma 2/Bcl‐2–associated X protein (Bcl‐2/Bax) ratio, suggesting that inhibition of COX‐2 sensitized human hepatoma cells to ER stress–induced apoptosis. Interestingly, co‐treatment with tunicamycin and melatonin also decreased the expression of COX‐2 and significantly increased the rate of apoptosis by elevating the levels of CHOP and reducing the Bcl‐2/Bax ratio. These results demonstrate that melatonin sensitizes human hepatoma cells to ER stress–induced apoptosis by down‐regulating COX‐2 expression, increasing the levels of CHOP and decreasing the Bcl‐2/Bax ratio.