title: FOXO3a-Dependent Mechanism of E1A-Induced Chemosensitization.
abstract: Gene therapy trials in human breast, ovarian, and head and neck tumors indicate that adenovirus E1A can sensitize cancer cells to the cytotoxic effects of paclitaxel in vitro and in vivo. Resistance to paclitaxel has been reported to occur in cells expressing low levels of the Forkhead transcription factor FOXO3a. In this article, we report that FOXO3a is critical for E1A-mediated chemosensitization to paclitaxel. RNA interference-mediated knockdown of FOXO3a abolished E1A-induced sensitivity to paclitaxel. Mechanistic investigations indicated that E1A indirectly stabilized FOXO3a by acting at an intermediate step to inhibit a ubiquitin-dependent proteolysis pathway involving the E3 ligase βTrCP and the FOXO3a inhibitory kinase IKKβ. E1A derepressed this inhibitory pathway by stimulating expression of the protein phosphatase 2A (PP2A)/C protein phosphatases, which by binding to the TGF-β-activated kinase TAK1, inhibited its ability to activate IKKβ and, thereby, to suppress βTrCP-mediated degradation of FOXO3a. Thus, by stimulating PP2A/C expression, E1A triggers a signaling cascade that stabilizes FOXO3a and mediates chemosensitization. Our findings provide a leap forward in understanding paclitaxel chemosensitization by E1A, and offer a mechanistic rational to apply E1A gene therapy as an adjuvant for improving therapeutic outcomes in patients receiving paclitaxel treatment.
authors.affiliation: Graduate Institute of Cancer Biology, College of Medicine, China Medical University, Taiwan.
authors.forename: Jen-Liang
authors.initials: JL
authors.lastname: Su
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Cheng
authors.forename: Hirohito
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Chang
authors.forename: Chao-Feng
authors.initials: CF
authors.lastname: Hou
authors.forename: Dung-Fang
authors.initials: DF
authors.lastname: Lee
authors.forename: How-Wen
authors.initials: HW
authors.lastname: Ko
authors.forename: Kuo-Tai
authors.initials: KT
authors.lastname: Hua
authors.forename: Ying-Nai
authors.initials: YN
authors.lastname: Wang
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.forename: Poshen B
authors.initials: PB
authors.lastname: Chen
authors.forename: Jung-Mao
authors.initials: JM
authors.lastname: Hsu
authors.forename: Robert C
authors.initials: RC
authors.lastname: Bast
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Hortobagyi
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology*; D017500:Adenovirus E1A Proteins / Q000502:physiology*; D000260:Adenoviruses, Human / Q000235:genetics; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor / Q000187:drug effects / Q000637:transplantation / Q000821:virology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000502:physiology / Q000627:therapeutic use; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D054648:Protein Phosphatase 2 / Q000378:metabolism; D055550:Protein Stability; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D025801:Ubiquitin / Q000502:physiology; D023041:Xenograft Model Antitumor Assays; D044844:beta-Transducin Repeat-Containing Proteins / Q000502:physiology; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D017500:Adenovirus E1A Proteins; D000911:Antibodies, Monoclonal; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D051550:I-kappa B Kinase; D020930:MAP Kinase Kinase Kinases; D009363:Neoplasm Proteins; D017239:Paclitaxel; D054648:Protein Phosphatase 2; D034741:RNA, Small Interfering; D025801:Ubiquitin; D044844:beta-Transducin Repeat-Containing Proteins; D000099151:MAP Kinase Kinase Kinase 7; C471644:BTRC protein, human; C499517:FOXO3 protein, human