Open AccessElongation factor‐2 kinase regulates TG 2/β1 integrin/Src/u PAR pathway and epithelial–mesenchymal transition mediating pancreatic cancer cells invasion
Author(s) -
Ashour Ahmed A.,
Gurbuz Nilgun,
Alpay Sultan Neslihan,
AbdelAziz AbdelAziz H.,
Mansour Ahmed M.,
Huo Longfei,
Ozpolat Bulent
Publication year - 2014
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12361
Subject(s) - rottlerin , biology , cancer research , epithelial–mesenchymal transition , gene silencing , pancreatic cancer , microbiology and biotechnology , metastasis , kinase , protein kinase a , cancer , biochemistry , genetics , gene
Pancreatic ductal adenocarcinoma is one of the lethal cancers with extensive local tumour invasion, metastasis, early systemic dissemination and poorest prognosis. Thus, understanding the mechanisms regulating invasion/metastasis and epithelial–mesenchymal transition ( EMT ), is the key for developing effective therapeutic strategies for pancreatic cancer (PaCa). Eukaryotic elongation factor‐2 kinase (e EF ‐2K) is an atypical kinase that we found to be highly up‐regulated in PaCa cells. However, its role in PaCa invasion/progression remains unknown. Here, we investigated the role of e EF ‐2K in cellular invasion, and we found that down‐regulation of e EF ‐2K, by si RNA or rottlerin, displays impairment of PaCa cells invasion/migration, with significant decreases in the expression of tissue transglutaminase ( TG 2), the multifunctional enzyme implicated in regulation of cell attachment, motility and survival. These events were associated with reductions in β1 integrin/u PAR / MMP ‐2 expressions as well as decrease in Src activity. Furthermore, inhibition of e EF ‐2K/ TG 2 axis suppresses the EMT , as demonstrated by the modulation of the zinc finger transcription factors, ZEB 1/Snail, and the tight junction proteins, claudins. Importantly, while e EF ‐2K silencing recapitulates the rottlerin‐induced inhibition of invasion and correlated events, e EF ‐2K overexpression, by lentivirus‐based expression system, suppresses such rottlerin effects and potentiates PaCa cells invasion/migration capability. Collectively, our results show, for the first time, that e EF ‐2K is involved in regulation of the invasive phenotype of PaCa cells through promoting a new signalling pathway, which is mediated by TG 2/β1 integrin/Src/u PAR / MMP ‐2, and the induction of EMT biomarkers which enhance cancer cell motility and metastatic potential. Thus, e EF ‐2K could represent a novel potential therapeutic target in pancreatic cancer.