The role of translational elongation loss in colorectal cancer


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Nikola Vlahov1,John Knight1,Owen Sansom1
1The Beatson Institute for Cancer Research

Abstract

Background

The elongation phase of mRNA translation is the most energy and amino acid consuming part of protein synthesis. This process is controlled by the Eukaryotic elongation factor 2 kinase (eEF2K), an atypical calmodulin-dependent protein kinase that slows down translation elongation by phosphorylating eEF2. eEF2K functions as a negative regulator of protein synthesis and cell growth. Cancer cells may possess mechanisms to inhibit eEF2K. We have previously shown that in colorectal cancer Rapamycin-induced reduction of elongation suppresses intestinal regeneration and tumourigenesis following APC loss. This process was shown to be controlled by eEF2K.

Method

We generated in vivo mouse models with acute deletion of either a single or both copies of Apc with either conditional expression of eEF2K kinase dead allele (D273A) or conditional deletion of eEF2K in the mouse intestine. We followed the rates of intestinal proliferation and tumourigenesis and the response to various drug therapies.

Results

In both of these models we observed loss of the inhibitory phosphorylation of eEF2. Intestinal crypt organoids from these mice showed increased ribosome run-off rate associated with inhibition of elongation control due to the loss of eEF2K function. We have also demonstrated that loss of eEF2K function or total eEF2K levels, following Apc loss, led to significant increase in survival compared to mice with Apc deletion alone. Deletion of eEF2K in addition to Apc and Kras, one of the most frequently altered genes following Apc, did not have an effect on survival.

Conclusion

We found that eEF2K deletion increases survival in mice that have lost Apc and we have explored the possibility to combine eEF2K inhibition with conventional drug treatments for colorectal cancer.