Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Apoptosis / genetics
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Cisplatin / pharmacology*
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Drug Resistance, Neoplasm / genetics
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Enzyme Activation / genetics
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Female
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Gene Expression
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Gene Expression Regulation, Neoplastic
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Humans
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JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
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JNK Mitogen-Activated Protein Kinases / genetics
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JNK Mitogen-Activated Protein Kinases / metabolism*
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Nuclear Proteins / genetics*
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Nuclear Proteins / metabolism
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Ovarian Neoplasms / genetics*
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Ovarian Neoplasms / metabolism*
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RNA Interference
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Signal Transduction / drug effects
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Tumor Protein p73
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Tumor Suppressor Proteins / genetics*
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Tumor Suppressor Proteins / metabolism
Substances
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Antineoplastic Agents
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Cell Cycle Proteins
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DNA-Binding Proteins
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GADD45A protein, human
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Nuclear Proteins
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TP73 protein, human
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Tumor Protein p73
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Tumor Suppressor Proteins
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JNK Mitogen-Activated Protein Kinases
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Cisplatin
Grants and funding
This research was jointly funded by the Wong Check She Charitable Foundation and the research fund from the Department of Obstetrics and Gynaecology, the University of Hong Kong. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.