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Gabitova L , Restifo D , Gorin A , Manocha K , Handorf E , Yang DH , Cai KQ , Klein-Szanto AJ , Cunningham D , Kratz LE , Herman GE , Golemis EA , Astsaturov I
Endogenous Sterol Metabolites Regulate Growth of EGFR/KRAS-Dependent Tumors via LXR
Cell Rep. 2015 Sep 22;12(11) :1927-38
PMID: 26344763    PMCID: PMC4581991    URL: https://www.ncbi.nlm.nih.gov/pubmed/26344763
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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 KRAS(G12D). 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) alpha. Importantly, EGFR signaling opposed LXRalpha effects on cholesterol homeostasis, whereas an EGFR inhibitor synergized with LXRalpha agonists in killing cancer cells. Inhibition of SC4MOL or NSDHL, or activation of LXRalpha by sterol metabolites, can be an effective strategy against carcinomas with activated EGFR-KRAS signaling.
Gabitova, Linara Restifo, Diana Gorin, Andrey Manocha, Kunal Handorf, Elizabeth Yang, Dong-Hua Cai, Kathy Q Klein-Szanto, Andres J Cunningham, David Kratz, Lisa E Herman, Gail E Golemis, Erica A Astsaturov, Igor K22 CA160725/CA/NCI NIH HHS/United States P30 CA006927/CA/NCI NIH HHS/United States R01 CA063366/CA/NCI NIH HHS/United States R01 CA080991/CA/NCI NIH HHS/United States R01 CA113342/CA/NCI NIH HHS/United States R01 CA188430/CA/NCI NIH HHS/United States R01 HD038572/HD/NICHD NIH HHS/United States R21 CA164205/CA/NCI NIH HHS/United States United States Cell Rep. 2015 Sep 22;12(11):1927-38. doi: 10.1016/j.celrep.2015.08.023. Epub 2015 Sep 3.