title: RIP kinase-mediated ROS production triggers XAF1 expression through activation of TAp73 in casticin-treated bladder cancer cells.
abstract: The p53 family protein p73 plays an important role in apoptosis induced by chemotherapeutic drugs. Transcriptionally active (TA) p73 (TAp73) substitutes for p53 in the response to stress. XIAP associated factor 1 (XAF1) is a novel predictive and prognostic factor in patients with bladder cancer, but the association between TAp73 and XAF1 expression in bladder cancer cells is poorly understood. Here, we investigated the status of TAp73 and XAF1 in T24 bladder cancer cells to identify molecular mechanisms in casticin‑exposed T24 cells. Casticin induced activation of JNK/p38 MAPK that preceded activation of the caspase cascade and disruption of the mitochondria membrane potential (∆ψm). Expression of XAF1 and TAp73 was also upregulated in casticin-treated T24 cells. Casticin treatment of T24 cells induced receptor-interacting protein (RIP) kinase expression and increased intracellular production of reactive oxygen species (ROS). Casticin-mediated ROS induced an increase in phosphorylated JNK/p38 MAPK, resulting in progressive upregulation of TAp73, which in turn led to XAF1 expression. Our data suggest that the apoptotic activity of casticin in T24 cells is mediated by activation of the TAp73-XAF1 signaling pathway through RIP kinase-mediated ROS production.
authors.affiliation: Department of Anatomy, Chung-Ang University College of Medicine, Seoul 06974, Republic of Korea.
authors.forename: Yoon Hee
authors.initials: YH
authors.lastname: Chung
authors.affiliation: Department of Anatomy, Inje University College of Medicine, Busan 47392, Republic of Korea.
authors.forename: Daejin
authors.initials: D
authors.lastname: Kim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D020169:Caspases / Q000235:genetics; D045744:Cell Line, Tumor; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics; D053078:Membrane Potential, Mitochondrial / Q000235:genetics; D008928:Mitochondria / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics*; D010766:Phosphorylation / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D000072160:Tumor Protein p73 / Q000235:genetics*; D016159:Tumor Suppressor Protein p53; D015854:Up-Regulation / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D005419:Flavonoids; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D017382:Reactive Oxygen Species; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; C417551:XAF1 protein, human; C054133:casticin; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases