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

doi:10.1016/j.celrep.2015.08.023

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

Kennedy Krieger Institute

Research output: Contribution to journal › Article › peer-review

45 Scopus citations

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) 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 language	English (US)
Pages (from-to)	1927-1938
Number of pages	12
Journal	Cell Reports
Volume	12
Issue number	11
DOIs	https://doi.org/10.1016/j.celrep.2015.08.023
State	Published - Sep 22 2015

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2015.08.023

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title = "Endogenous Sterol Metabolites Regulate Growth of EGFR/KRAS-Dependent Tumors via LXR",

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.",

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

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year = "2015",

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doi = "10.1016/j.celrep.2015.08.023",

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T1 - Endogenous Sterol Metabolites Regulate Growth of EGFR/KRAS-Dependent Tumors via LXR

AU - Gabitova, Linara

AU - Restifo, Diana

AU - Gorin, Andrey

AU - Manocha, Kunal

AU - Handorf, Elizabeth

AU - Yang, Dong Hua

AU - Cai, Kathy Q.

AU - Klein-Szanto, Andres J.

AU - Cunningham, David

AU - Kratz, Lisa E.

AU - Herman, Gail E.

AU - Golemis, Erica A.

AU - Astsaturov, Igor

PY - 2015/9/22

Y1 - 2015/9/22

N2 - 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.

AB - 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.

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

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