Abstract
Tumor protein (TP)-p53 family members (TP63, TP63 and TP73) are guardians of the genome and key players in orchestrating the cellular response to cisplatin treatment. Cisplatin-induced phosphorylation of ΔNp63α was shown to have a role in regulating intracellular ΔNp63α protein levels. We previously found that squamous cell carcinoma (SCC) cells exposed to cisplatin displayed the ATM-dependent phosphorylation of ΔNp63α (p-ΔNp63α), which is critical for the transcriptional regulation of specific downstream mRNAs and microRNAs and is likely to underlie the chemoresistance of SCC cells. However, SCC cells expressing non-p-ΔNp63α became more cisplatin-resistant. We also found that p-ΔNp63α forms complexes with a number of proteins involved in cell death response through regulation of cell cycle arrest, apoptosis, autophagy, RNA splicing and chromatin modifications. Here, we showed that p-ΔNp63α induced ARG1, GAPDH, and CPT2 gene transcription in cisplatin-sensitive SCC cells, while non-p-ΔNp63α increased a transcription of CAD, G6PD and FASN genes in cisplatin-resistant SCC cells. We report that the p-ΔNp63α-dependent regulatory mechanisms implicated in the modulation of plethora of pathways, including amino acid, carbohydrate, lipid and nucleotide metabolisms, thereby affect tumor cell response to cisplatin-induced cell death, suggesting that the ATM-dependent ΔNp63α pathway plays a role in the resistance of tumor cells to platinum therapy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology
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Ataxia Telangiectasia Mutated Proteins
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Carcinoma, Squamous Cell / drug therapy
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Carcinoma, Squamous Cell / genetics*
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Carcinoma, Squamous Cell / metabolism
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Cell Cycle Checkpoints / drug effects
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Cell Cycle Proteins / antagonists & inhibitors
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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 / antagonists & inhibitors
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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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Gene Expression Regulation, Neoplastic
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Genes, Reporter
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Head and Neck Neoplasms / drug therapy
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Head and Neck Neoplasms / genetics*
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Head and Neck Neoplasms / metabolism
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Humans
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Luciferases
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / genetics*
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Neoplasm Proteins / metabolism
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Phosphorylation / drug effects
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Protein Binding
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / genetics*
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Protein Serine-Threonine Kinases / metabolism
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Signal Transduction / drug effects
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Sterol Regulatory Element Binding Protein 1 / genetics
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Sterol Regulatory Element Binding Protein 1 / metabolism
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Transfection
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Tumor Suppressor Proteins / antagonists & inhibitors
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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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Neoplasm Proteins
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SREBF1 protein, human
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Sterol Regulatory Element Binding Protein 1
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TP63 protein, human
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Transcription Factors
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Tumor Suppressor Proteins
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Luciferases
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Protein Serine-Threonine Kinases
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Cisplatin