TAp73-mediated the activation of c-Jun N-terminal kinase enhances cellular chemosensitivity to cisplatin in ovarian cancer cells

• Published in: PloS one Vol. 7; no. 8; p. e42985
• Main Authors: Zhang, Pingde, Liu, Stephanie Si, Ngan, Hextan Yuen Sheung
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10.08.2012; Public Library of Science (PLoS)
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; BAX protein; Biology; c-Jun protein; Cancer; Cancer cells; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Deoxyribonucleic acid; DNA; DNA damage; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Drug Resistance, Neoplasm - genetics; Enzyme Activation - genetics; Female; GADD45 protein; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Inhibition; JNK Mitogen-Activated Protein Kinases - antagonists & inhibitors; JNK Mitogen-Activated Protein Kinases - genetics; JNK Mitogen-Activated Protein Kinases - metabolism; JNK protein; Kinases; MAP kinase; Medicine; Mitogens; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Ovarian cancer; Ovarian carcinoma; Ovarian Neoplasms - genetics; Ovarian Neoplasms - metabolism; p53 Protein; Protein kinase; Protein kinases; Ribonucleic acid; RNA; RNA Interference; Signal transduction; Signal Transduction - drug effects; Signaling; siRNA; Structure-function relationships; Transcription factors; Tumor Protein p73; Tumor proteins; Tumor suppressor genes; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Hong Kong China; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0042985

P73, one member of the tumor suppressor p53 family, shares highly structural and functional similarity to p53. Like p53, the transcriptionally active TAp73 can mediate cellular response to chemotherapeutic agents in human cancer cells by up-regulating the expressions of its pro-apoptotic target genes such as PUMA, Bax, NOXA. Here, we demonstrated a novel molecular mechanism for TAp73-mediated apoptosis in response to cisplatin in ovarian cancer cells, and that was irrespective of p53 status. We found that TAp73 acted as an activator of the c-Jun N-terminal kinase (JNK) signaling pathway by up-regulating the expression of its target growth arrest and DNA-damage-inducible protein GADD45 alpha (GADD45α) and subsequently activating mitogen-activated protein kinase kinase-4 (MKK4). Inhibition of JNK activity by a specific inhibitor or small interfering RNA (siRNA) significantly abrogated TAp73-mediated apoptosis induced by cisplatin. Furthermore, inhibition of GADD45α by siRNA inactivated MKK4/JNK activities and also blocked TAp73-mediated apoptosis induction by cisplatin. Our study has demonstrated that TAp73 activated the JNK apoptotic signaling pathway in response to cisplatin in ovarian cancer cells.