Endogenous Sterol Metabolites Regulate Growth of EGFR/KRAS-Dependent Tumors via LXR

Linara Gabitova, Diana Restifo, Andrey Gorin, Kunal Manocha, Elizabeth Handorf, Dong Hua Yang, Kathy Q. Cai, Andres J. Klein-Szanto, David Cunningham, Lisa E. Kratz, Gail E. Herman, Erica A. Golemis, Igor Astsaturov

Research output: Contribution to journalArticle

Abstract

Meiosis-activating sterols (MAS) are substrates of SC4MOL and NSDHL in the cholesterol pathway and are important for normal organismal development. Oncogenic transformation by epidermal growth factor receptor (EGFR) or RAS increases the demand for cholesterol, suggesting a possibility for metabolic interference. To test this idea in vivo, we ablated Nsdhl in adult keratinocytes expressing KRASG12D. Strikingly, Nsdhl inactivation antagonized the growth of skin tumors while having little effect on normal skin. Loss of Nsdhl induced the expression of ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, reduced the expression of low-density lipoprotein receptor (LDLR), decreased intracellular cholesterol, and was dependent on the liver X receptor (LXR) α. Importantly, EGFR signaling opposed LXRα effects on cholesterol homeostasis, whereas an EGFR inhibitor synergized with LXRα agonists in killing cancer cells. Inhibition of SC4MOL or NSDHL, or activation of LXRα by sterol metabolites, can be an effective strategy against carcinomas with activated EGFR-KRAS signaling.

Original languageEnglish (US)
Pages (from-to)1927-1938
Number of pages12
JournalCell Reports
Volume12
Issue number11
DOIs
StatePublished - Sep 22 2015

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Gabitova, L., Restifo, D., Gorin, A., Manocha, K., Handorf, E., Yang, D. H., Cai, K. Q., Klein-Szanto, A. J., Cunningham, D., Kratz, L. E., Herman, G. E., Golemis, E. A., & Astsaturov, I. (2015). Endogenous Sterol Metabolites Regulate Growth of EGFR/KRAS-Dependent Tumors via LXR. Cell Reports, 12(11), 1927-1938. https://doi.org/10.1016/j.celrep.2015.08.023