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Myc Expression Drives Aberrant Lipid Metabolism in Lung Cancer

Published version
Peer-reviewed

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Authors

Ament, Z 
Wilson, CH 
Burkhart, DL 
Ashmore, T 

Abstract

MYC-mediated pathogenesis in lung cancer continues to attract interest for new therapeutic strategies. In this study, we describe a transgenic mouse model of KRAS-driven lung adenocarcinoma that affords reversible activation of MYC, used here as a tool for lipidomic profiling of MYC-dependent lung tumors formed in this model. Advanced mass spectrometric imaging and surface analysis techniques were used to characterize the spatial and temporal changes in lipid composition in lung tissue. We found that normal lung tissue was characterized predominantly by saturated phosphatidylcholines and phosphatidylglycerols, which are major lipid components of pulmonary surfactant. In contrast, tumor tissues displayed an increase in phosphatidylinositols and arachidonate-containing phospholipids that can serve as signaling precursors. Deactivating MYC resulted in a rapid and dramatic decrease in arachidonic acid and its eicosanoid metabolites. In tumors with high levels of MYC, we found an increase in cytosolic phospholipase A2 (cPLA2) activity with a preferential release of membrane-bound arachidonic acid, stimulating the lipoxygenase (LOX) and COX pathways also amplified by MYC at the level of gene expression. Deactivating MYC lowered cPLA2 activity along with COX2 and 5-LOX mRNA levels. Notably, inhibiting the COX/5-LOX pathways in vivo reduced tumor burden in a manner associated with reduced cell proliferation. Taken together, our results show how MYC drives the production of specific eicosanoids critical for lung cancer cell survival and proliferation, with possible implications for the use of COX and LOX pathway inhibitors for lung cancer therapy.

Description

Keywords

Adenocarcinoma, Adenocarcinoma of Lung, Animals, Disease Models, Animal, Eicosanoids, Immunohistochemistry, Lipid Metabolism, Lung Neoplasms, Mass Spectrometry, Mice, Mice, Transgenic, Polymerase Chain Reaction, Proto-Oncogene Proteins c-myc, Proto-Oncogene Proteins p21(ras), Signal Transduction, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Journal Title

Cancer Research

Conference Name

Journal ISSN

0008-5472
1538-7445

Volume Title

76

Publisher

American Association for Cancer Research
Sponsorship
Medical Research Council (MR/P011705/1)
Medical Research Council (MC_PC_13030)
This research was funded by the Medical Research Council (Lipid Profiling and Signaling, MC UP A90 1006 & Lipid Dynamics and Regulation, MC PC 13030) and Cancer Research UK (program grant A12077).