title: P62 regulates resveratrol-mediated Fas/Cav-1 complex formation and transition from autophagy to apoptosis.
abstract: Resveratrol is a potential polyphenol drug used in cancer treatment. We examined the relationship between autophagy and apoptosis in RSV-treated non-small lung adenocarcinoma A549 cells. Resveratrol treatment increased autophagy and autophagy-mediated degradation of P62. Immunocytochemistry revealed P62 co-localized with Fas/Cav-1 complexes, known to induce apoptosis. However, siRNA-mediated P62 downregulation enhanced formation of Fas/Cav-1 complexes, suggesting that P62 inhibited Fas/Cav-1 complex formation. Fas/Cav-1 complexes triggered caspase-8 activation and cleavage of Beclin-1, releasing a C-terminal Beclin-1 peptide that translocated to the mitochondria and initiate apoptosis. Inhibition of autophagy by siRNA-mediated repression of Beclin-1 also blocked RSV-induced apoptosis, showing a dependence of apoptosis on autophagy. P62 knockdown by siRNA accelerated the activation of caspase-8 and initiate apoptosis, while Cav-1 knockdown inhibited apoptosis, but increased autophagy. Inhibition of autophagy by 3-MA prevented both P62 degradation and induction of apoptosis, whereas inhibition of apoptosis by z-IETD-FMK or z-DEVD-FMK enhanced both P62 induction and autophagic cell death. In conclusion, P62 links resveratrol-induced autophagy to apoptosis. P62 blocks apoptosis by inhibiting Fas/Cav-1 complex formation, but RSV-induced autophagic degradation of P62 enables formation of Fas/Cav-1 complexes which then activate caspase-8-mediated Beclin-1 cleavage, resulting in translocation of the Beclin-1 C-terminal fragment to the mitochondria to initiate apoptosis.
authors.affiliation: Open Laboratory for Tumor Molecular Biology/Department of Biochemistry, The Key Lab of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Open Laboratory for Tumor Molecular Biology/Department of Biochemistry, The Key Lab of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Ma
authors.affiliation: Open Laboratory for Tumor Molecular Biology/Department of Biochemistry, The Key Lab of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Qi
authors.affiliation: Open Laboratory for Tumor Molecular Biology/Department of Biochemistry, The Key Lab of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Wei
authors.affiliation: Open Laboratory for Tumor Molecular Biology/Department of Biochemistry, The Key Lab of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Open Laboratory for Tumor Molecular Biology/Department of Biochemistry, The Key Lab of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China.
authors.forename: Guanwu
authors.initials: G
authors.lastname: Li
authors.affiliation: Open Laboratory for Tumor Molecular Biology/Department of Biochemistry, The Key Lab of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China.
authors.forename: Jen-Fu
authors.initials: JF
authors.lastname: Chiu
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051242:Caveolin 1 / Q000096:biosynthesis / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D014162:Transfection; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D051242:Caveolin 1; C498779:IGF2BP2 protein, human; C118585:P62 protein, human; D016601:RNA-Binding Proteins; D013267:Stilbenes; D019014:fas Receptor; D000077185:Resveratrol