Phospho-ΔNp63α/SREBF1 protein interactions: bridging cell metabolism and cisplatin chemoresistance.

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.

• Authors: Yiping Huang, Lauren N Bell, Jun Okamura, Myoung Soo Kim, Robert P Mohney, Rafael Guerrero-Preston, Edward A Ratovitski
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 11 Issue 20 Pg. 3810-27 (Oct 15 2012) ISSN: 1551-4005 [Electronic] United States
• PMID: 22951905 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cell Cycle Proteins
• DNA-Binding Proteins
• Neoplasm Proteins
• SREBF1 protein, human
• Sterol Regulatory Element Binding Protein 1
• TP63 protein, human
• Transcription Factors
• Tumor Suppressor Proteins
• Luciferases
• ATM protein, human
• Ataxia Telangiectasia Mutated Proteins
• Protein Serine-Threonine Kinases
• Cisplatin

Topics

• Antineoplastic Agents (pharmacology)
• Ataxia Telangiectasia Mutated Proteins
• Carcinoma, Squamous Cell (drug therapy, genetics, metabolism)
• Cell Cycle Checkpoints (drug effects)
• Cell Cycle Proteins (antagonists & inhibitors, genetics, metabolism)
• Cell Line, Tumor
• Cisplatin (pharmacology)
• DNA-Binding Proteins (antagonists & inhibitors, genetics, metabolism)
• Drug Resistance, Neoplasm (genetics)
• Gene Expression Regulation, Neoplastic
• Genes, Reporter
• Head and Neck Neoplasms (drug therapy, genetics, metabolism)
• Humans
• Luciferases
• Neoplasm Proteins (antagonists & inhibitors, genetics, metabolism)
• Phosphorylation (drug effects)
• Protein Binding
• Protein Serine-Threonine Kinases (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction (drug effects)
• Sterol Regulatory Element Binding Protein 1 (genetics, metabolism)
• Transcription Factors (genetics, metabolism)
• Transfection
• Tumor Suppressor Proteins (antagonists & inhibitors, genetics, metabolism)