Does modifying energy metabolism alter cellular signaling and proliferation in KRAS mutant NSCLCs?

Abstract Objectives The capacity to sense and respond to cellular energy stress is an important factor in tumorigenesis. We aimed to investigate the proliferation patterns of KRAS-mutant NSCLC cell lines (A549, Calu-1, H2009) under high (HG) and low glucose (LG) conditions w/wo DCA, which alters metabolic pathways and promotes oxidative phosphorylation. Methods Cell viability was detected by MTT assay, protein expressions were determined by Western Blot and RNA expressions were analyzed by RT-qPCR. Results NSCLCs exhibited lower proliferation in HG compared to LG conditions. The effect of DCA in reducing the proliferation of the cells, was higher in HG compared to LG condition. We detected lower pRB levels in LG and in DCA treated conditions. LG conditions also showed higher p21 levels w/wo DCA while AMPK activation was more pronounced in 48 h. p-JAK2 was dominant in conditions having LG and p-Stat3 activation varied between all cells. The eIF4e activation was induced in LG w/wo DCA in all the cells. Despite p21-mediated cell cycle arrest, eIF4e and JAK2 signaling promoted proliferation. Conclusions Our results clearly showed the potential for increased aggressiveness and the delicate balance of cellular metabolic adjustments in response to energy stress in KRAS-mutant NSCLC cells.