Abstract
KRASG12C is among the most common oncogenic mutations in lung adenocarcinoma and a promising target for treatment by small-molecule inhibitors. KRAS oncogenic signaling is responsible for modulation of tumor microenvironment, with translation factors being among the most prominent deregulated targets. In the present study, we used TALENs to edit EGFRWT CL1-5 and A549 cells for integration of a Tet-inducible KRASG12C expression system. Subsequent analysis of both cell lines showed that cap-dependent translation was impaired in CL1-5 cells via involvement of mTORC2 and NF-κB. In contrast, in A549 cells, which additionally harbor the KRASG12S mutation, cap-dependent translation was favored via recruitment of mTORC1, c-MYC and the positive regulation of eIF4F complex. Downregulation of eIF1, eIF5 and eIF5B in the same cell line suggested a stringency loss of start codon selection during scanning of mRNAs. Puromycin staining and polysome profile analysis validated the enhanced translation rates in A549 cells and the impaired cap-dependent translation in CL1-5 cells. Interestingly, elevated translation rates were restored in CL1-5 cells after prolonged induction of KRASG12C through an mTORC1/p70S6K-independent way. Collectively, our results suggest that KRASG12C signaling differentially affects the regulation of the translational machinery. These differences could provide additional insights and facilitate current efforts to effectively target KRAS.
Highlights
Oncogenic mutations detected in EGFR (15–50%) or KRAS (20–30%) activate either MAPK and/or PI3K/AKT/mTOR signaling pathways, which, in turn, target important translation initiation factors [1]
Our results suggest that the net effect of KRASG12C expression in A549 cells is the promotion of cap-dependent translation, which is in good agreement with previous reports suggesting that KRAS mutations can promote cap-dependent translation (Figure 5A) [34,35]
P-values are inOduicratreedsuwlittshs*upg
Summary
Oncogenic mutations detected in EGFR (15–50%) or KRAS (20–30%) activate either MAPK and/or PI3K/AKT/mTOR signaling pathways, which, in turn, target important translation initiation factors [1]. KRAS alleles have been associated with differences in the biochemical properties, structural conformation and biological activity of each mutant These differences account for the different clinical phenotypes of KRASdriven tumors, the prognostic value of the specific codon mutations and the response to first-line chemotherapy treatment, which vary between different cancer types and genomic contexts [4]. It was shown recently that mutant KRAS can rewire the metabolic process of cancer cells by transcriptionally activating NRF2, leading to acquired chemoresistance that can be effectively targeted [9]. In lung adenocarcinoma, a clear picture of the specific modulation of translation initiation driven by specific KRAS mutations is limited
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