Endogenous Sterol Metabolites Regulate Growth of EGFR/KRAS-Dependent Tumors via LXR.
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.
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Tatarstan 420000, Russia.
Linara
L
Gabitova
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Diana
D
Restifo
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Tatarstan 420000, Russia.
Andrey
A
Gorin
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Kunal
K
Manocha
Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Elizabeth
E
Handorf
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Dong-Hua
DH
Yang
Histopathology Facility, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Kathy Q
KQ
Cai
Histopathology Facility, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Andres J
AJ
Klein-Szanto
The Research Institute at Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA.
David
D
Cunningham
Kennedy Krieger Institute, Johns Hopkins University, Baltimore, MD 21205, USA.
Lisa E
LE
Kratz
The Research Institute at Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA.
Gail E
GE
Herman
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Erica A
EA
Golemis
Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Tatarstan 420000, Russia. Electronic address: igor.astsaturov@fccc.edu.
Igor
I
Astsaturov
D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D006801:Humans; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors / Q000819:agonists; D010212:Papilloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013261:Sterols / Q000378:metabolism*; D014162:Transfection
D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D013261:Sterols; D002784:Cholesterol; D015096:3-Hydroxysteroid Dehydrogenases; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras)