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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) 12:1927-38.
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 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.
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Publication Date: 2015-09-22.
PMCID: PMC4581991
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Last updated on Saturday, August 22, 2020