Involvement of melatonin in autophagy-mediated mouse hepatoma H22 cell survival.
The role of autophagy in cancer is controversial. Melatonin has been linked to several aspects of cancer progression and also to regulation of autophagy. Whether melatonin is involved in an autophagy-induced tumor suppressor mechanism or a cyto-protective mechanism is unknown. Therefore, we investigated the effects of melatonin on autophagy and its upstream regulator. We found that melatonin triggers an autophagic process by enhancing Beclin 1 expression and inducing a conversion of microtubule-associated protein 1 light chain 3(LC3)-I to LC3-II, the protein associated with the autophagosome membrane, in hepatoma H22 tumor-bearing mice. Moreover, melatonin inhibits the phosphorylation of the mammalian target of the rapamycin (mTOR) and Akt. Knockdown of Beclin 1 by either RNA interference or co-treatment with the autophagy inhibitor, 3-methyladenine(3-MA), significantly enhanced the melatonin-induced apoptosis in mouse hepatoma H22 cells. Our data provides the first evidence that melatonin induces protective autophagy that prevents mouse hepatoma H22 cells from undergoing apoptosis. A combination of melatonin with an autophagy inhibitor might be a useful therapeutic strategy for hepatocellular carcinoma.
Department of Medical Oncology, The Military General Hospital of Beijing PLA, Beijing, China.
Chang
C
Liu
Zhiling
Z
Jia
Xia
X
Zhang
Jincai
J
Hou
Li
L
Wang
Shuling
S
Hao
Xinjian
X
Ruan
Zhonghe
Z
Yu
Yongqiu
Y
Zheng
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D000071186:Beclin-1; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; C025946:3-methyladenine; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000225:Adenine; D008550:Melatonin