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

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-δ 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 (ΔΨm), 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-δ 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 ROT-induced 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.

• Authors: Ahmed A Ashour, Abdel-Aziz H Abdel-Aziz, Ahmed M Mansour, S Neslihan Alpay, Longfei Huo, Bulent Ozpolat
• Journal: Apoptosis : an international journal on programmed cell death (Apoptosis) Vol. 19 Issue 1 Pg. 241-58 (Jan 2014) ISSN: 1573-675X [Electronic] Netherlands
• PMID: 24193916 (Publication Type: Journal Article)

Chemical References

• Acetophenones
• Antineoplastic Agents
• Apoptosis Inducing Factor
• Benzopyrans
• rottlerin
• Elongation Factor 2 Kinase

Topics

• Acetophenones (pharmacology)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Apoptosis Inducing Factor (genetics, metabolism)
• Benzopyrans (pharmacology)
• Cell Line, Tumor
• Elongation Factor 2 Kinase (antagonists & inhibitors, genetics, metabolism)
• Humans
• Pancreatic Neoplasms (drug therapy, enzymology, genetics, physiopathology)
• Signal Transduction (drug effects)