DNp63a Confers Tumor Cell Resistance to Cisplatin through the AKT1 Transcriptional Regulation

Strategies to address resistance to platin drugs are greatly needed in human epithelial cancers (e.g., ovarian, head/neck, and lung) where platins are used widely and resistance occurs commonly. We found that upon DNp63a overexpression, AKT1 and phospho-AKT1 levels are upregulated in cancer cells. Investigations using gel-shift, chromatin immunoprecipitation and functional reporter assays implicated DNp63a in positive regulation of AKT1 transcription. Importantly, we found that DNp63a, AKT1, and phospho-AKT levels are greater in 2008CI3 CDDP-resistant ovarian cancer cells than in 2008 CDDP-sensitive cells. siRNA-mediated knockdown of DNp63a expression dramatically decreased AKT1 expression, whereas knockdown of either DNp63a or AKT1 decreased cell proliferation and increased death of ovarian and head/neck cancer cells. Conversely, enforced expression of DNp63a increased cancer cell proliferation and reduced apoptosis. Together, our findings define a novel DNp63a-dependent regulatory mechanism for AKT1 expression and its role in chemotherapeutic resistance of ovarian and head/neck cancer cells. Cancer Res; 71(3); 1167–76. 2011 AACR.