DeltaNp63alpha-mediated induction of epidermal growth factor receptor promotes pancreatic cancer cell growth and chemoresistance.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to current chemotherapy regimens, in part due to alterations in the p53 tumor suppressor pathway. p53 homolog p63 is a transcription factor essential for the development and differentiation of epithelial surfaces. However its function in cancer is controversial and its role in PDAC is not known. We discovered that ?Np63? was the predominantly expressed p63 variant in pancreatic cancer cell lines. ?Np63? protein and mRNA levels were high in T3M4, BxPC3 and COLO-357 pancreatic cancer cells and low in ASPC-1 and PANC-1 cells. Overexpression of ?Np63? in PANC-1 cells and shRNA-mediated knockdown in T3M4 cells indicated that ?Np63? promoted anchorage-dependent and -independent growth, motility and invasion, and enhanced resistance to cisplatin-induced apoptosis. Epidermal growth factor receptor (EGFR) signaling pathways contribute to the biological aggressiveness of PDAC, and we found that the motogenic effects of ?Np63? were augmented in presence of EGF. Ectopic expression of ?Np63? resulted in upregulation of EGFR and ?1-integrin in PANC-1 cells. Conversely, ?Np63? knockdown had an opposite effect in T3M4 cells. ?Np63? potentiated EGF-mediated activation of ERK, Akt and JNK signaling. Chromatin immunoprecipitation and functional reporter assays demonstrated that ?Np63? activated EGFR transcription. 14-3-3? transcription was also positively regulated by ?Np63? and we have previously shown that 14-3-3? contributes to chemoresistance in pancreatic cancer cell lines. Conversely, shRNA-mediated knockdown of 14-3-3? led to abrogation of the ?Np63? effects on cell proliferation and invasion. Thus, p53 homolog ?Np63? enhances the oncogenic potential of pancreatic cancer cells through trans-activation of EGFR and 14-3-3?.

SUBMITTER: Danilov AV 

PROVIDER: S-EPMC3203907 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature