title: The prosurvival role of autophagy in resveratrol-induced cytotoxicity in GH3 cells.
abstract: In a previous study, we reported that resveratrol exerts antitumor effects through the estrogen receptor in prolactinoma. The autophagy/lysosomal degradation pathway plays an important role in damage control and energy efficiency. In this study, we investigated the involvement of autophagy and the related signaling pathways in resveratrol-induced apoptosis of GH3 cells. We demonstrate that resveratrol inhibits cell proliferation and induces apoptosis in a dose-dependent manner in GH3 cells. The cleavage of PARP was also observed, and the activation of caspase-3 and caspase-8 was detected. Consistent with this finding, the inhibition of caspase activation effectively attenuated resveratrol-induced cell apoptosis. In addition, the decreased level of Bcl-2 was also observed. The induction of autophagy was confirmed by the detection of the formation of autophagic vacuoles, and the increase in microtubule-associated protein 1 light chain 3 (LC3)-II and beclin-1 levels, two hallmarks of autophagy. Pre-treatment with bafilomycin A1 or 3-methyladenine, inhibitors of autophagy, enhanced the resveratrol-mediated caspase activation and cell death. Moreover, resveratrol induced the activation of ERK1/2, as well as the downregulation of Akt and mTOR phosphorylation. Taken together, these findings indicate that resveratrol induces caspase-dependent apoptosis and decreases Bcl-2 levels. In addition, resveratrol-induced autophagy is regulated by the PI3K/Akt/mTOR and ERK1/2 pathways. Furthermore, the inhibition of autophagy increases the cytotoxicity of resveratrol to GH3 cells.
authors.affiliation: Department of Neurosurgery, The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Xuexin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Urology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Wanhai
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Neurosurgery, The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Su
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Chu
authors.affiliation: Department of Neurosurgery, The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Hua
authors.initials: H
authors.lastname: Jin
authors.affiliation: Department of Neurosurgery, The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Guofu
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Chunlei
authors.initials: C
authors.lastname: Tan
authors.affiliation: Department of Neurosurgery, The Third Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D020169:Caspases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D000077185:Resveratrol; D013267:Stilbenes; D058570:TOR Serine-Threonine Kinases