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Melatonin overcomes apoptosis resistance in human hepatocellular carcinoma by targeting S urvivin and XIAP
Author(s) -
Fan Lulu,
Sun Guoping,
Ma Tai,
Zhong Fei,
Wei Wei
Publication year - 2013
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/jpi.12060
Subject(s) - xiap , hepatocellular carcinoma , melatonin , apoptosis , medicine , cancer research , biology , biochemistry , caspase , programmed cell death
Apoptosis resistance in hepatocellular carcinoma ( HCC ) is one of the most significant factors for hepatocarcinogenesis and tumor progression, and leads to resistance to conventional chemotherapy. It is well known that inhibitor of apoptosis proteins ( IAP s) play key roles in apoptosis resistance, it has become an important target for antitumor therapy. In this study, we examined if melatonin, the main secretory product of the pineal gland, targeted IAP s, leading to the inhibition of apoptosis resistance. To accomplish this, we first observed that four members of IAP s ( cIAP ‐1, cIAP ‐2, S urvivin, and XIAP ) were overexpressed in human HCC tissue. Interestingly, melatonin significantly inhibited the growth of H epG2 and SMMC ‐7721 cells and promoted apoptosis along with the downregulation of Survivin and XIAP , but had no effect on the expression of cIAP ‐1 and cIAP ‐2. These data suggest that the inhibition of S urvivin and XIAP by melatonin may play an important part in reversing apoptosis resistance. Notably, cIAP ‐1, S urvivin and XIAP were significantly associated with the coexpression of COX ‐2 in human HCC specimens. Melatonin also reduced the expression of COX ‐2 and inhibited AKT activation in H epG2 and SMMC ‐7721 cells. Inhibition of COX ‐2 activity with the selective inhibitor, NS398, and inhibition of AKT activation using the P I3K inhibitor, LY294002, in tumor cells confirmed that melatonin‐induced apoptosis was COX ‐2/PI3K/AKT‐dependent, suggesting that the COX ‐2/PI3K/AKT pathway plays a role in melatonin inhibition of IAP s. Taken together, these results suggest that melatonin overcomes apoptosis resistance by the suppressing S urvivin and XIAP via the COX ‐2/PI3K/AKT pathway in HCC cells.