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Mol Cancer Ther. 2014 Oct;13(10):2361-71. doi: 10.1158/1535-7163.MCT-14-0183. Epub 2014 Aug 13.

Lipid catabolism via CPT1 as a therapeutic target for prostate cancer.

Author information

1
Department of Pharmacology, University of Colorado Denver, Aurora, Colorado. isabel.schlaepfer@ucdenver.edu.
2
Department of Pharmacology, University of Colorado Denver, Aurora, Colorado.
3
Department of Pathology, Wake Forest University School of Medicine Winston-Salem, North Carolina.
4
Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Aurora, Colorado.
5
Division of Endocrinology Metabolism and Diabetes, Department of Medicine, University of Colorado Denver, Aurora, Colorado.

Abstract

Prostate cancer is the most commonly diagnosed malignancy among Western men and accounts for the second leading cause of cancer-related deaths. Prostate cancer tends to grow slowly and recent studies suggest that it relies on lipid fuel more than on aerobic glycolysis. However, the biochemical mechanisms governing the relationships between lipid synthesis, lipid utilization, and cancer growth remain unknown. To address the role of lipid metabolism in prostate cancer, we have used etomoxir and orlistat, clinically safe drugs that block lipid oxidation and lipid synthesis/lipolysis, respectively. Etomoxir is an irreversible inhibitor of the carnitine palmitoyltransferase (CPT1) enzyme that decreases β oxidation in the mitochondria. Combinatorial treatments using etomoxir and orlistat resulted in synergistic decreased viability in LNCaP, VCaP, and patient-derived benign and prostate cancer cells. These effects were associated with decreased androgen receptor expression, decreased mTOR signaling, and increased caspase-3 activation. Knockdown of CPT1A enzyme in LNCaP cells resulted in decreased palmitate oxidation but increased sensitivity to etomoxir, with inactivation of AKT kinase and activation of caspase-3. Systemic treatment with etomoxir in nude mice resulted in decreased xenograft growth over 21 days, underscoring the therapeutic potential of blocking lipid catabolism to decrease prostate cancer tumor growth.

PMID:
25122071
PMCID:
PMC4185227
DOI:
10.1158/1535-7163.MCT-14-0183
[Indexed for MEDLINE]
Free PMC Article

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