Vitamin D and SIRT1 activator SRT2104 cooperate in antiproliferative activity in lung cancer through ferroptosis induction

A number of studies showed that vitamin D reveals antiproliferative activity against cancer cells, however some lung cancer cells are more sensitive than others. Secondly, there are some controversies around the role of SIRT1 in lung cancer: on one hand it was demonstrated that SIRT1 contributed to the development of lung cancer, on the other hand SIRT1 was showed to be downregulated in lung cancer. Third, it was demonstrated that VDR is posttranslationally modified via deacetylation by SIRT1 what potentiated VDR activity. In this study, we first showed an inverse correlation between VDR and SIRT1 expression level in lung cancer. We further revealed that vitamin D and SIRT1 activator SRT2104 cooperate in inhibiting lung cancer cells proliferation. SRT2104 enhanced transcriptional activity of calcitriol in lung cancer cells, since the expression of CYP24A1 was significantly higher after the treatment with calcitriol and SRT2104 compared with calcitriol alone. Calcitriol and SRT2104 affected the metabolic rate of lung cancer cells, increased ROS and superoxide production, decreased GSH/GSSG ratio and induced lipid peroxidation. Calcitriol and SRT2104 also significantly induced the expression of COX-2 and reduced the level of Hsp90 and mutp53 in EGFR mutant lung cancer cells. The study showed that the use of calcitriol in combination with SRT2104 SIRT1 activator shows stronger antitumor activity in lung cancer. This effect may be due to the induction of ferroptosis. These insights pave the way for potential to use SIRT1 activators with vitamin D derivatives in the treatment of lung cancer. • An inverse correlation between VDR and SIRT1 expression level was identified in lung cancer cells. • SIRT1 activator SRT2104 enhanced the antiproliferative effect of calcitriol. • Calcitriol and SRT2104 increased ROS and superoxide levels, reduced GSH/GSSG ratio, induced lipid peroxidation, and thus ferroptosis. • Calcitriol and SRT2104 upregulated COX-2 expression while decreasing Hsp90 and mutp53 levels in EGFR mutant LUAD cells. • SIRT1 activators in combination with vitamin D are promising candidates in the treatment of lung cancer.