Targeting elongation factor-2 kinase (eEF-2K) induces apoptosis in human pancreatic cancer cells

Ahmed A. Ashour, Abdel Aziz H. Abdel-Aziz, Ahmed M. Mansour, S. Neslihan Alpay, Longfei Huo, Bulent Ozpolat

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

Pancreatic cancer (PaCa) is one of the most aggressive, apoptosis-resistant and currently incurable cancers with a poor survival rate. Eukaryotic elongation factor-2 kinase (eEF-2K) is an atypical kinase, whose role in PaCa survival is not yet known. Here, we show that eEF- 2K is overexpressed in PaCa cells and its down-regulation induces apoptotic cell death. Rottlerin (ROT), a polyphenolic compound initially identified as a PKC-d inhibitor, induces apoptosis and autophagy in a variety of cancer cells including PaCa cells. We demonstrated that ROT induces intrinsic apoptosis, with dissipation of mitochondrial membrane potential (DWm), and stimulates extrinsic apoptosis with concomitant induction of TNF-related apoptosis inducing ligand (TRAIL) receptors, DR4 and DR5, with caspase-8 activation, in PANC-1 and MIAPaCa- 2 cells. Notably, while none of these effects were dependent on PKC-d inhibition, ROT down-regulates eEF- 2K at mRNA level, and induce eEF-2K protein degradation through ubiquitin-proteasome pathway. Down-regulation of eEF-2K recapitulates the events observed after ROT treatment, while its over-expression suppressed the ROTinduced apoptosis. Furthermore, eEF-2K regulates the expression of tissue transglutaminase (TG2), an enzyme previously implicated in proliferation, drug resistance and survival of cancer cells. Inhibition of eEF-2K/TG2 axis leads to caspase-independent apoptosis which is associated with induction of apoptosis-inducing factor (AIF). Collectively, these results indicate, for the first time, that the down-regulation of eEF-2K leads to induction of intrinsic, extrinsic as well as AIF-dependent apoptosis in PaCa cells, suggesting that eEF-2K may represent an attractive therapeutic target for the future anticancer agents in PaCa.

Original languageEnglish (US)
Pages (from-to)241-258
Number of pages18
JournalApoptosis
Volume19
Issue number1
DOIs
StatePublished - Jan 2014

Keywords

  • Apoptosis
  • Eef-2k
  • Pancreatic cancer
  • Pkc delta
  • Rottlerin
  • Tg2

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Clinical Biochemistry
  • Cell Biology
  • Biochemistry, medical
  • Cancer Research

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