ΔNp63α 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 Delta Np63 alpha overexpression, AKT1 and phospho-AKT1 levels are upregulated in cancer cells. Investigations using gel-shift, chromatin immunoprecipitation and functional reporter assays implicated Delta Np63 alpha in positive regulation of AKT1 transcription. Importantly, we found that Delta Np63 alpha, AKT1, and phospho-AKT levels are greater in 2008CI3 CDDP-resistant ovarian cancer cells than in 2008 CDDP-sensitive cells. siRNA-mediated knockdown of Delta Np63 alpha expression dramatically decreased AKT1 expression, whereas knockdown of either Delta Np63 alpha or AKT1 decreased cell proliferation and increased death of ovarian and head/neck cancer cells. Conversely, enforced expression of Delta Np63 alpha increased cancer cell proliferation and reduced apoptosis. Together, our findings define a novel Delta Np63 alpha-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. (C) 2011 AACR.