Phospho-ΔNp63α/Rpn13-dependent regulation of LKB1 degradation modulates autophagy in cancer cells

Oxidativue 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 Delta Np63 alpha in squamous cell carcinoma (SCC) cells. In this study, phosphorylated (p)-Delta Np63 alpha was shown to bind the ATM promoter, to increase the ATM promoter activity and to enhance the ATM cytoplasmic accumulation. P-Delta Np63 alpha protein was further shown to interact with the Rpn13 protein leading to a proteasome-dependent degradation of p-Delta Np63 alpha and thereby protecting LKB1 from the degradation. In SCC cells (with an altered ability to support the ATM-dependent Delta Np63 alpha phosphorylation), the non-phosphorylated Delta Np63 alpha 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-Delta Np63 alpha/non-phosphorylated Delta Np63 alpha 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-Delta Np63 alpha or LKB1 to be targeted for degradation is critical for cell death decision made by cancer cells in response to chemotherapy.