<i>Rpl24^Bst</i> mutation suppresses colorectal cancer by promoting eEF2 phosphorylation via eEF2K.

Abstract

Increased protein synthesis supports the rapid cell proliferation associated with cancer. The <i>Rpl24^Bst</i> mutant mouse reduces the expression of the ribosomal protein RPL24 and has been used to suppress translation and limit tumorigenesis in multiple mouse models of cancer. Here, we show that <i>Rpl24^Bst</i> also suppresses tumorigenesis and proliferation in a model of colorectal cancer (CRC) with two common patient mutations, <i>Apc</i> and <i>Kras</i>. In contrast to previous reports, <i>Rpl24^Bst</i> mutation has no effect on ribosomal subunit abundance but suppresses translation elongation through phosphorylation of eEF2, reducing protein synthesis by 40% in tumour cells. Ablating eEF2 phosphorylation in <i>Rpl24^Bst</i> mutant mice by inactivating its kinase, eEF2K, completely restores the rates of elongation and protein synthesis. Furthermore, eEF2K activity is required for the <i>Rpl24^Bst</i> mutant to suppress tumorigenesis. This work demonstrates that elevation of eEF2 phosphorylation is an effective means to suppress colorectal tumorigenesis with two driver mutations. This positions translation elongation as a therapeutic target in CRC, as well as in other cancers where the <i>Rpl24^Bst</i> mutation has a tumour suppressive effect in mouse models.