Eukaryotic elongation factor 2 kinase upregulates the expression of proteins implicated in cell migration and cancer cell metastasis

• Published in: International journal of cancer 2018-05, Vol.142 (9), p.1865-1877
• Main Authors: Xie, Jianling, Shen, Kaikai, Lenchine, Roman V., Gethings, Lee A., Trim, Paul J., Snel, Marten F., Zhou, Ying, Kenney, Justin W., Kamei, Makoto, Kochetkova, Marina, Wang, Xuemin, Proud, Christopher G.
• Format: Article
• Language: English
• Subjects: A549 Cells; Animals; Breast Neoplasms - enzymology; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cell adhesion & migration; Cell Line, Tumor; Cell migration; Cell Movement - physiology; eEF2K; Elongation; Elongation Factor 2 Kinase - biosynthesis; Elongation Factor 2 Kinase - genetics; Elongation Factor 2 Kinase - metabolism; Heterografts; Humans; Inhibition; Integrins; Invasiveness; Kinases; Lung cancer; Lung carcinoma; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Male; Medical research; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Mice, Knockout; Mice, Nude; migration; mRNA; Neoplasm Invasiveness; Neoplasm Metastasis; Polyribosomes; Protein Biosynthesis; Protein synthesis; Proteins; RNA, Messenger - genetics; Therapeutic applications; translation; Translation elongation; Tumor cells; Tumors; Up-Regulation; Wound healing
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.31210

Eukaryotic elongation factor 2 kinase (eEF2K) negatively regulates the elongation phase of mRNA translation and hence protein synthesis. Increasing evidence indicates that eEF2K plays an important role in the survival and migration of cancer cells and in tumor progression. As demonstrated by two‐dimensional wound‐healing and three‐dimensional transwell invasion assays, knocking down or inhibiting eEF2K in cancer cells impairs migration and invasion of cancer cells. Conversely, exogenous expression of eEF2K or knocking down eEF2 (the substrate of eEF2K) accelerates wound healing and invasion. Importantly, using LC‐HDMSE analysis, we identify 150 proteins whose expression is decreased and 73 proteins which are increased upon knocking down eEF2K in human lung carcinoma cells. Of interest, 34 downregulated proteins are integrins and other proteins implicated in cell migration, suggesting that inhibiting eEF2K may help prevent cancer cell mobility and metastasis. Interestingly, eEF2K promotes the association of integrin mRNAs with polysomes, providing a mechanism by which eEF2K may enhance their cellular levels. Consistent with this, genetic knock down or pharmacological inhibition of eEF2K reduces the protein expression levels of integrins. Notably, pharmacological or genetic inhibition of eEF2K almost completely blocked tumor growth and effectively prevented the spread of tumor cells in vivo. High levels of eEF2K expression were associated with invasive carcinoma and metastatic tumors. These data provide the evidence that eEF2K is a new potential therapeutic target for preventing tumor metastasis. What's new? New results show how a protein involved in translation helps cancer cells travel. Eukaryotic elongation factor 2 (eEF2) moves the ribosome along the mRNA strand, and eEF2K impairs its ability to do this. Previous reports note that many cancers produce copious eEF2K, and that blocking it inhibits cell migration. Here, the authors show that reducing eEF2K in the lung cancer cells cuts expression of some 34 proteins needed for cell migration. They further showed that in mice, inhibiting eEF2K stops the growth and spread of tumors. Targeting eEF2K, they propose, could be a fruitful strategy for thwarting metastasis.