DeltaNp63alpha confers tumor cell resistance to cisplatin through the AKT1 transcriptional regulation.

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Sen T, Sen N, Brait M, Begum S, Chatterjee A, Hoque MO, Ratovitski E, Sidransky D

DeltaNp63alpha confers tumor cell resistance to cisplatin through the AKT1 transcriptional regulation.

Cancer Res. 2011 Feb 1;71(3):1167-76. doi: 10.1158/0008-5472.CAN-10-1481. Epub 2011 Jan 25.

PubMed ID

21266360 [ View in PubMed

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Abstract

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 DeltaNp63alpha overexpression, AKT1 and phospho-AKT1 levels are upregulated in cancer cells. Investigations using gel-shift, chromatin immunoprecipitation and functional reporter assays implicated DeltaNp63alpha in positive regulation of AKT1 transcription. Importantly, we found that DeltaNp63alpha, AKT1, and phospho-AKT levels are greater in 2008CI3 CDDP-resistant ovarian cancer cells than in 2008 CDDP-sensitive cells. siRNA-mediated knockdown of DeltaNp63alpha expression dramatically decreased AKT1 expression, whereas knockdown of either DeltaNp63alpha or AKT1 decreased cell proliferation and increased death of ovarian and head/neck cancer cells. Conversely, enforced expression of DeltaNp63alpha increased cancer cell proliferation and reduced apoptosis. Together, our findings define a novel DeltaNp63alpha-dependent regulatory mechanism for AKT1 expression and its role in chemotherapeutic resistance of ovarian and head/neck cancer cells.