title: The XAF1 tumor suppressor induces autophagic cell death via upregulation of Beclin-1 and inhibition of Akt pathway.
abstract: Autophagy is designated as type II programmed cell death and may confer a tumor-suppressive function. Our previous studies have shown that XIAP-associated factor 1 (XAF1) induced apoptosis and inhibited tumor growth in gastric cancer cells. In this study, we investigated the effect of XAF1 on the induction of autophagy in gastric cancer cells. We found that adenovirus vector-mediated XAF1 (adeno-XAF1) expression markedly induced autophagy, upregulated the level of Beclin-1 and inhibited phospho-Akt and phospho-p70S6K in gastric cancer cells. The downregulation of Beclin 1 or 3-methyladenine treatment suppressed adeno-XAF1-induced autophagy, but significantly enhanced adeno-XAF1-induced apoptosis. A pan-caspase inhibitor prevented adeno-XAF1-induced apoptosis, but significantly increased adeno-XAF1-induced autophagy. Furthermore, adeno-XAF1 induced autophagy in xenograft tumor and inhibited tumor growth. Our results document that adeno-XAF1 induces autophagy through upregulation of Beclin 1 expression and inhibition of Akt/p70S6K pathway, and reveal a new mechanism of XAF1 tumor suppression.
authors.affiliation: Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, People's Republic of China.
authors.forename: Ping Hu
authors.initials: PH
authors.lastname: Sun
authors.forename: Li Ming
authors.initials: LM
authors.lastname: Zhu
authors.forename: Min Min
authors.initials: MM
authors.lastname: Qiao
authors.forename: Yong Ping
authors.initials: YP
authors.lastname: Zhang
authors.forename: Shi Hu
authors.initials: SH
authors.lastname: Jiang
authors.forename: Yun Lin
authors.initials: YL
authors.lastname: Wu
authors.forename: Shui Ping
authors.initials: SP
authors.lastname: Tu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000235:genetics*; D000071186:Beclin-1; D045744:Cell Line, Tumor; D005260:Female; D016147:Genes, Tumor Suppressor; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D014162:Transfection; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; C417551:XAF1 protein, human; D051057:Proto-Oncogene Proteins c-akt