{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T02:00:45Z","timestamp":1770688845396,"version":"3.49.0"},"reference-count":37,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2013,5,25]],"date-time":"2013-05-25T00:00:00Z","timestamp":1369440000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Pineal Research"],"published-print":{"date-parts":[[2013,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Chemoresistance in hepatocellular carcinoma (<jats:styled-content style=\"fixed-case\">HCC<\/jats:styled-content>) is associated with multiple cellular responses to environmental stresses, such as nutrient deprivation and hypoxia. Nevertheless, whether<jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content>stress resulting from nutrient deprivation and tumor hypoxia contributes to drug resistance remains unclear. Melatonin increased the efficacy of chemotherapeutic drugs in hepatocellular carcinoma in our previous studies. However, the effects of melatonin on endoplasmic reticulum (<jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content>) stress\u2010induced resistance to chemotherapeutic agents in<jats:styled-content style=\"fixed-case\">HCC<\/jats:styled-content>have not been tested. The effect of the endoplasmic reticulum (<jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content>) stress response during resistance of human hepatocellular carcinoma cells against doxorubicin was investigated in this study. Pretreatment of HepG2 and<jats:styled-content style=\"fixed-case\">SMMC<\/jats:styled-content>\u20107721 cells (two human hepatocellular carcinoma cell lines) with tunicamycin, an<jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content>stress inducer, drastically decreased the rate of apoptosis generated by doxorubicin. Interestingly, co\u2010pretreatment with tunicamycin and melatonin significantly increased apoptosis induced by doxorubicin. Simultaneously, the expression of phosphorylated<jats:styled-content style=\"fixed-case\">AKT<\/jats:styled-content>(p\u2010<jats:styled-content style=\"fixed-case\">AKT<\/jats:styled-content>) was elevated in HepG2 and<jats:styled-content style=\"fixed-case\">SMMC<\/jats:styled-content>\u20107721 cells given tunicamycin but reduced in the presence of melatonin. Furthermore, consistent with inhibition of<jats:styled-content style=\"fixed-case\">AKT<\/jats:styled-content>activation by using the<jats:styled-content style=\"fixed-case\">PI<\/jats:styled-content>3K inhibitor<jats:styled-content style=\"fixed-case\">LY<\/jats:styled-content>294002, melatonin elevated the levels of<jats:styled-content style=\"fixed-case\">CHOP<\/jats:styled-content>(C\/<jats:styled-content style=\"fixed-case\">EBP<\/jats:styled-content>\u2010homologous protein) and reduced the levels of Survivin (a member of the inhibitor of apoptosis protein family)suggesting that inhibition of the<jats:styled-content style=\"fixed-case\">PI<\/jats:styled-content>3K\/<jats:styled-content style=\"fixed-case\">AKT<\/jats:styled-content>pathway by melatonin\u2010reversed<jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content>stress\u2010induced resistance to doxorubicin in human hepatocellular carcinoma cells. These results demonstrate that melatonin attenuates<jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content>stress\u2010induced resistance to doxorubicin in human hepatocellular carcinoma cells by down\u2010regulating the<jats:styled-content style=\"fixed-case\">PI<\/jats:styled-content>3K\/<jats:styled-content style=\"fixed-case\">AKT<\/jats:styled-content>pathway, increasing the levels of<jats:styled-content style=\"fixed-case\">CHOP<\/jats:styled-content>and decreasing the levels of Survivin.<\/jats:p>","DOI":"10.1111\/jpi.12061","type":"journal-article","created":{"date-parts":[[2013,4,24]],"date-time":"2013-04-24T07:36:45Z","timestamp":1366789005000},"page":"184-194","source":"Crossref","is-referenced-by-count":64,"title":["Melatonin reverses tunicamycin\u2010induced endoplasmic reticulum stress in human hepatocellular carcinoma cells and improves cytotoxic response to doxorubicin by increasing<scp>CHOP<\/scp>and decreasing 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