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It is well known that inhibitor of apoptosis proteins (<jats:styled-content style=\"fixed-case\">IAP<\/jats:styled-content>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 <jats:styled-content style=\"fixed-case\">IAP<\/jats:styled-content>s, leading to the inhibition of apoptosis resistance. To accomplish this, we first observed that four members of <jats:styled-content style=\"fixed-case\">IAP<\/jats:styled-content>s (<jats:styled-content style=\"fixed-case\">cIAP<\/jats:styled-content>\u20101, <jats:styled-content style=\"fixed-case\">cIAP<\/jats:styled-content>\u20102, <jats:styled-content style=\"fixed-case\">S<\/jats:styled-content>urvivin, and <jats:styled-content style=\"fixed-case\">XIAP<\/jats:styled-content>) were overexpressed in human <jats:styled-content style=\"fixed-case\">HCC<\/jats:styled-content> tissue. Interestingly, melatonin significantly inhibited the growth of <jats:styled-content style=\"fixed-case\">H<\/jats:styled-content>epG2 and <jats:styled-content style=\"fixed-case\">SMMC<\/jats:styled-content>\u20107721 cells and promoted apoptosis along with the downregulation of Survivin and <jats:styled-content style=\"fixed-case\">XIAP<\/jats:styled-content>, but had no effect on the expression of <jats:styled-content style=\"fixed-case\">cIAP<\/jats:styled-content>\u20101 and <jats:styled-content style=\"fixed-case\">cIAP<\/jats:styled-content>\u20102. These data suggest that the inhibition of <jats:styled-content style=\"fixed-case\">S<\/jats:styled-content>urvivin and <jats:styled-content style=\"fixed-case\">XIAP<\/jats:styled-content> by melatonin may play an important part in reversing apoptosis resistance. Notably, <jats:styled-content style=\"fixed-case\">cIAP<\/jats:styled-content>\u20101, <jats:styled-content style=\"fixed-case\">S<\/jats:styled-content>urvivin and <jats:styled-content style=\"fixed-case\">XIAP<\/jats:styled-content> were significantly associated with the coexpression of <jats:styled-content style=\"fixed-case\">COX<\/jats:styled-content>\u20102 in human <jats:styled-content style=\"fixed-case\">HCC<\/jats:styled-content> specimens. Melatonin also reduced the expression of <jats:styled-content style=\"fixed-case\">COX<\/jats:styled-content>\u20102 and inhibited <jats:styled-content style=\"fixed-case\">AKT<\/jats:styled-content> activation in <jats:styled-content style=\"fixed-case\">H<\/jats:styled-content>epG2 and <jats:styled-content style=\"fixed-case\">SMMC<\/jats:styled-content>\u20107721 cells. Inhibition of <jats:styled-content style=\"fixed-case\">COX<\/jats:styled-content>\u20102 activity with the selective inhibitor, NS398, and inhibition of <jats:styled-content style=\"fixed-case\">AKT<\/jats:styled-content> activation using the <jats:styled-content style=\"fixed-case\">P<\/jats:styled-content>I3K inhibitor, LY294002, in tumor cells confirmed that melatonin\u2010induced apoptosis was <jats:styled-content style=\"fixed-case\">COX<\/jats:styled-content>\u20102\/PI3K\/AKT\u2010dependent, suggesting that the <jats:styled-content style=\"fixed-case\">COX<\/jats:styled-content>\u20102\/PI3K\/AKT pathway plays a role in melatonin inhibition of <jats:styled-content style=\"fixed-case\">IAP<\/jats:styled-content>s. Taken together, these results suggest that melatonin overcomes apoptosis resistance by the suppressing <jats:styled-content style=\"fixed-case\">S<\/jats:styled-content>urvivin and <jats:styled-content style=\"fixed-case\">XIAP<\/jats:styled-content> via the <jats:styled-content style=\"fixed-case\">COX<\/jats:styled-content>\u20102\/PI3K\/AKT pathway in <jats:styled-content style=\"fixed-case\">HCC<\/jats:styled-content> cells.<\/jats:p>","DOI":"10.1111\/jpi.12060","type":"journal-article","created":{"date-parts":[[2013,4,24]],"date-time":"2013-04-24T07:36:44Z","timestamp":1366789004000},"page":"174-183","source":"Crossref","is-referenced-by-count":62,"title":["Melatonin overcomes apoptosis resistance in human hepatocellular carcinoma by targeting <scp>S<\/scp>urvivin and <scp>XIAP<\/scp>"],"prefix":"10.1111","volume":"55","author":[{"given":"Lulu","family":"Fan","sequence":"first","affiliation":[{"name":"Department of Oncology The First Affiliated Hospital of Anhui Medical University Hefei Anhui China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guoping","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Oncology The First Affiliated Hospital of Anhui Medical University Hefei Anhui China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tai","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Oncology The First Affiliated Hospital of Anhui Medical University Hefei Anhui China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fei","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Oncology The First Affiliated Hospital of Anhui Medical University Hefei Anhui China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Wei","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacology Anhui Medical University Hefei Anhui 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