Ceramide Kinase Inhibition Drives Ferroptosis and Sensitivity to Cisplatin in Mutant KRAS Lung Cancer by Dysregulating VDAC-Mediated Mitochondria Function

Author:

Vu Ngoc T.12,Kim Minjung1ORCID,Stephenson Daniel J.13,MacKnight H. Patrick13ORCID,Chalfant Charles E.13456ORCID

Affiliation:

1. 1Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, Tampa, Florida.

2. 2Institute of Biotechnology and Food Technology, Industrial University of Ho Chi Minh City, Ho Chi Minh City, Vietnam.

3. 3Division of Hematology and Oncology, Department of Medicine, University of Virginia, Charlottesville, Virginia.

4. 4Department of Cell Biology, University of Virginia, Charlottesville, Virginia.

5. 5Program in Cancer Biology, University of Virginia Cancer Center, Charlottesville, Virginia.

6. 6Research Service, Richmond Veterans Administration Medical Center, Richmond Virginia.

Abstract

Abstract 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. Implications: Our findings depict how CERK inhibition may serve as a new key point in combination therapeutic strategy for NSCLC, specifically precision therapeutics targeting NSCLC possessing a KRAS mutation.

Funder

National Institutes of Health—National Institute of Allergy and Infectious Diseases

National Institute of General Medical Sciences

Veteran's Administration

Senior Research Career Scientist Award

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology,Molecular Biology

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