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 specifc 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 modifcations. 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 afect 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. © 2012 Landes Bioscience.