Phospho-ΔNp63α/SREBF1 protein interactions Bridging cell metabolism and cisplatin chemoresistance

Tumor protein (TP)-p53 family members (TP 63, TP 63 and TP 73) are guardians of the genome and key players in orchestrating the cellular response to cisplatin treatment. Cisplatin-induced phosphorylation of Delta Np63 alpha was shown to have a role in regulating intracellular Delta Np63 alpha protein levels. We previously found that squamous cell carcinoma (SCC) cells exposed to cisplatin displayed the ATM-dependent phosphorylation of Delta Np63 alpha (p-Delta Np63 alpha), 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-Delta Np63 alpha became more cisplatin-resistant. We also found that p-Delta Np63 alpha 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-Delta Np63 alpha induced ARG1, GAPDH, and CPT2 gene transcription in cisplatin-sensitive SCC cells, while non-p-Delta Np63 alpha increased a transcription of CAD, G6PD and FASN genes in cisplatin-resistant SCC cells. We report that the p-Delta Np63 alpha-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 Delta Np63 alpha pathway plays a role in the resistance of tumor cells to platinum therapy.