Abstract
Oxidative stress was shown to promote the translocation of Ataxia-telangiectasia mutated (ATM) to cytoplasm and trigger the LKB1-AMPK-tuberin pathway leading to a down-regulation of mTOR and subsequently inducing the programmed cell death II (autophagy). Cisplatin was previously found to induce the ATM-dependent phosphorylation of ΔNp63α in squamous cell carcinoma (SCC) cells. In this study, phosphorylated (p)-ΔNp63α was shown to bind the ATM promoter, to increase the ATM promoter activity and to enhance the ATM cytoplasmic accumulation. P-ΔNp63α protein was further shown to interact with the Rpn13 protein leading to a proteasome-dependent degradation of p-ΔNp63α and thereby protecting LKB1 from the degradation. In SCC cells (with an altered ability to support the ATM-dependent ΔNp63α phosphorylation), the non-phosphorylated ΔNp63α protein failed to form protein complexes with the Rpn13 protein and thereby allowing the latter to bind and target LKB1 into a proteasome-dependent degradation pathway thereby modulating a cisplatin-induced autophagy. We thus suggest that SCC cells sensitive to cisplatin-induced cell death are likely to display a greater ratio of p-ΔNp63α/non-phosphorylated ΔNp63α than cells with the innate resistant/impaired response to a cisplatin-induced cell death. Our data also suggest that the choice made by Rpn13 between p-ΔNp63α or LKB1 to be targeted for degradation is critical for cell death decision made by cancer cells in response to chemotherapy.
Highlights
Cisplatin is the most applicable drug for treating various human cancers, its efficiency is limited due to development of drug resistance by tumor cells [1,2,3]
To access the role for pΔNp63α in the regulation of Ataxia‐telangiectasia mutated (ATM) expression under DNA damage, we employed the cellular model, isogenic squamous cell carcinoma (SCC) clones, which contain the genomic copy of wild type ΔNp6α or ΔNp63α-S385G
These clones were used as tools to examine the role for phosphorylation of ΔNp63α in transcriptional regulation of gene expression and in the cellular response to chemotherapeutic treatment allowing us to define novel gene targets involved in cisplatin-mediated resistance [4, 5]
Summary
Cisplatin is the most applicable drug for treating various human cancers, its efficiency is limited due to development of drug resistance by tumor cells [1,2,3]. That the cisplatin treatment significantly increased the ATM promoter-driven luciferase activity in wild type ΔNp63α cells (by ~4.01+0.34 fold), while no such effect (by ~1.06+0.12) was observed in ΔNp63α-S385G cells upon cisplatin exposure (Fig. 2B). The levels of cytoplasmic ATM and activated TSC2 were significantly increased, while mTOR protein levels were decreased in wild type wild type ΔNp63α cells upon cisplatin exposure (Fig. 3A, left panel).
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