Endogenous Sterol Metabolites Regulate Growth of EGFR/KRAS-Dependent Tumors via LXR.
Cell Rep
; 12(11): 1927-38, 2015 Sep 22.
Article
em En
| MEDLINE
| ID: mdl-26344763
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Esteróis
/
Colesterol
/
Proteínas Proto-Oncogênicas p21(ras)
/
Receptores ErbB
Limite:
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
Cell Rep
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Federação Russa