Loading...
Endogenous Sterol Metabolites Regulate Growth of EGFR/KRAS-Dependent Tumors via LXR
Gabitova, Linara Restifo, Diana Gorin, Andrey Manocha, Kunal Handorf, Elizabeth A. Yang, Dong-Hua Cai, Kathy Q. Klein-Szanto, Andres Cunningham, David Kratz, Lisa E.
Gabitova, Linara
Restifo, Diana
Gorin, Andrey
Manocha, Kunal
Handorf, Elizabeth A.
Yang, Dong-Hua
Cai, Kathy Q.
Klein-Szanto, Andres
Cunningham, David
Kratz, Lisa E.
An error occurred retrieving the object's statistics
Citations
Altmetric:
Genre
Journal article
Date
2015-09-22
Advisor
Committee member
Department
Cancer and Cellular Biology
Subject
Permanent link to this record
Collections
Research Projects
Organizational Units
Journal Issue
DOI
http://dx.doi.org/10.1016/j.celrep.2015.08.023
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.
Description
Citation
Gabitova L, Restifo D, Gorin A, Manocha K, Handorf EA, Yang D-H, et al. Endogenous Sterol Metabolites Regulate Growth of EGFR/KRAS-Dependent Tumors via LXR. Cell Rep. 2015 Sep 22;12(11):1927-1938. doi:10.1016/j.celrep.2015.08.023.
Citation to related work
Cell Press
Has part
Cell Reports, Vol. 12, Iss. 11
ADA compliance
For Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu