Suppression of acetylpolyamine oxidase by selected AP-1 members regulates DNp73 abundance: mechanistic insights for overcoming DNp73-mediated resistance to chemotherapeutic drugs.
Enhanced resistance to chemotherapy has been correlated with high levels of Delta-Np73 (DNp73), an anti-apoptotic protein of the p53 tumor-suppressor family which inhibits the pro-apoptotic members such as p53 and TAp73. Although genotoxic drugs have been shown to induce DNp73 degradation, lack of mechanistic understanding of this process precludes strategies to enhance the targeting of DNp73 and improve treatment outcomes. Antizyme (Az) is a mediator of ubiquitin-independent protein degradation regulated by the polyamine biosynthesis pathway. We show here that acetylpolyamine oxidase (PAOX), a catabolic enzyme of this pathway, upregulates DNp73 levels by suppressing its degradation via the Az pathway. Conversely, downregulation of PAOX activity by siRNA-mediated knockdown or chemical inhibition leads to DNp73 degradation in an Az-dependent manner. PAOX expression is suppressed by several genotoxic drugs, via selected members of the activator protein-1 (AP-1) transcription factors, namely c-Jun, JunB and FosB, which are required for stress-mediated DNp73 degradation. Finally, chemical- and siRNA-mediated inhibition of PAOX significantly reversed the resistant phenotype of DNp73-overexpressing cancer cells to genotoxic drugs. Together, these data define a critical mechanism for the regulation of DNp73 abundance, and reveal that inhibition of PAOX could widen the therapeutic index of cytotoxic drugs and overcome DNp73-mediated chemoresistance in tumors.
Laboratory of Molecular Carcinogenesis, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, 11, Hospital Drive, Singapore, Singapore.
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Bunjobpol
Laboratory of Molecular Carcinogenesis, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, 11, Hospital Drive, Singapore, Singapore.
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Dulloo
Amine Pharma Research Institute, Innovation Plaza at Chiba University, 1-8-15Inohana, Chiba, Japan.
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Igarashi
Department of Obstetrics and Gynecology, Innsbruck Medical University, Anichstrasse 35, Innsbruck, Austria.
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Concin
Department of Microbiology and Immunology, School of Medicine, Keio University, 35 Shinanomachi, Tokyo, Japan.
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Matsuo
1] Laboratory of Molecular Carcinogenesis, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, 11, Hospital Drive, Singapore, Singapore [2] Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8, College Road, Singapore, Singapore [3] Department of Biochemistry, National University of Singapore, 8, Medical Drive, Singapore, Singapore.
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Sabapathy
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D045325:HCT116 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000378:metabolism*; D015398:Signal Transduction; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D015854:Up-Regulation; D000097667:Polyamine Oxidase
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000587:Oxidoreductases Acting on CH-NH Group Donors; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D000097667:Polyamine Oxidase; C000606368:Trp73 protein, mouse; C000606369:delta Np73 protein, human