4.7 Article

KRASG12C Can Either Promote or Impair Cap-Dependent Translation in Two Different Lung Adenocarcinoma Cell Lines

Journal

Publisher

MDPI
DOI: 10.3390/ijms22042222

Keywords

KRAS(G12C); signal transduction; translation initiation; lung cancer

Funding

  1. INSPIRED - Operational Program Competitiveness, Entrepreneurship and Innovation (NSRF 2014-2020) [MIS 5002550]
  2. General Secretariat for Research and Technology (GSRT)
  3. Hellenic Foundation for Research and Innovation (HFRI)
  4. Fulbright Doctoral Dissertation Visiting Research Student Fellowship (2018-2019)
  5. State Scholarships Foundation (IKY)
  6. European Union (European Regional Development Fund)

Ask authors/readers for more resources

The study reveals that the KRAS(G12C) signaling pathway has differential effects on the translational machinery in CL1-5 cells and A549 cells, leading to changes in translation rates and cap-dependent translation.
KRAS(G12C) 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 EGFR(WT) CL1-5 and A549 cells for integration of a Tet-inducible KRAS(G12C) 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-kappa B. In contrast, in A549 cells, which additionally harbor the KRAS(G12S) 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 KRAS(G12C) through an mTORC1/p70S6K-independent way. Collectively, our results suggest that KRAS(G12C) signaling differentially affects the regulation of the translational machinery. These differences could provide additional insights and facilitate current efforts to effectively target KRAS.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available