%0 Journal Article
%T DeltaNp63alpha-Mediated Induction of Epidermal Growth Factor Receptor Promotes Pancreatic Cancer Cell Growth and Chemoresistance
%A Alexey V. Danilov
%A Divas Neupane
%A Archana Sidalaghatta Nagaraja
%A Elena V. Feofanova
%A Leigh Ann Humphries
%A James DiRenzo
%A Murray Korc
%J PLOS ONE
%D 2011
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0026815
%X 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¦Á was the predominantly expressed p63 variant in pancreatic cancer cell lines. ¦¤Np63¦Á 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¦Á in PANC-1 cells and shRNA-mediated knockdown in T3M4 cells indicated that ¦¤Np63¦Á 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¦Á were augmented in presence of EGF. Ectopic expression of ¦¤Np63¦Á resulted in upregulation of EGFR and ¦Â1-integrin in PANC-1 cells. Conversely, ¦¤Np63¦Á knockdown had an opposite effect in T3M4 cells. ¦¤Np63¦Á potentiated EGF-mediated activation of ERK, Akt and JNK signaling. Chromatin immunoprecipitation and functional reporter assays demonstrated that ¦¤Np63¦Á activated EGFR transcription. 14-3-3¦Ò transcription was also positively regulated by ¦¤Np63¦Á and we have previously shown that 14-3-3¦Ò contributes to chemoresistance in pancreatic cancer cell lines. Conversely, shRNA-mediated knockdown of 14-3-3¦Ò led to abrogation of the ¦¤Np63¦Á effects on cell proliferation and invasion. Thus, p53 homolog ¦¤Np63¦Á enhances the oncogenic potential of pancreatic cancer cells through trans-activation of EGFR and 14-3-3¦Ò.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0026815