期刊
MOLECULAR CANCER RESEARCH
卷 20, 期 9, 页码 1429-1442出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-22-0085
关键词
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资金
- National Institutes of Health - National Institute of Allergy and Infectious Diseases [R01 AI139072]
- National Institute of General Medical Sciences [R01 GM137578]
- Senior Research Career Scientist Award [IK6BX004603]
- [I BX001792]
This study reveals that CERK inhibition induces ferroptosis in mutant KRAS NSCLC cells by modulating VDAC, leading to reduced cell survival. Additionally, CERK inhibition synergizes with cisplatin to inhibit in vivo tumor growth in NSCLC.
Ceramide kinase (CERK) is the mammalian lipid kinase from which the bioactive sphingolipid, ceramide-1-phosphate (C1P), is derived. CERK has been implicated in several promalignant phenotypes with little known as to mechanistic underpinnings. In this study, the mechanism of how CERK inhibition decreases cell survival in mutant (Mut) KRAS non-small cell lung cancer (NSCLC), a major lung cancer subtype, was revealed. Specifically, NSCLC cells possessing a KRAS mutation were more responsive to inhibition, downregulation, and genetic ablation of CERK compared with those with wild-type (WT) KRAS regarding a reduction in cell survival. Inhibition of CERK induced ferroptosis in Mut KRAS NSCLC cells, which required elevating VDAC-regulated mitochondria membrane potential (MMP) and the generation of cellular reactive oxygen species (ROS). Importantly, through modulation of VDAC, CERK inhibition synergized with the first-line NSCLC treatment, cisplatin, in reducing cell survival and in vivo tumor growth. Further mechanistic studies indicated that CERK inhibition affected MMP and cell survival by limiting AKT activation and translocation to mitochondria, and thus, blocking VDAC phosphorylation and tubulin recruitment.
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