title: Lipid catabolism via CPT1 as a therapeutic target for prostate cancer.
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.
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Aurora, Colorado. isabel.schlaepfer@ucdenver.edu.
authors.forename: Isabel R
authors.initials: IR
authors.lastname: Schlaepfer
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Aurora, Colorado.
authors.forename: Leah
authors.initials: L
authors.lastname: Rider
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Aurora, Colorado.
authors.forename: Lindsey Ulkus
authors.initials: LU
authors.lastname: Rodrigues
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Aurora, Colorado.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Gijón
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Aurora, Colorado.
authors.forename: Colton T
authors.initials: CT
authors.lastname: Pac
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Aurora, Colorado.
authors.forename: Lina
authors.initials: L
authors.lastname: Romero
authors.affiliation: Department of Pathology, Wake Forest University School of Medicine Winston-Salem, North Carolina.
authors.forename: Adela
authors.initials: A
authors.lastname: Cimic
authors.affiliation: Department of Pathology, Wake Forest University School of Medicine Winston-Salem, North Carolina.
authors.forename: S Joseph
authors.initials: SJ
authors.lastname: Sirintrapun
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Aurora, Colorado.
authors.forename: L Michael
authors.initials: LM
authors.lastname: Glodé
authors.affiliation: Division of Endocrinology Metabolism and Diabetes, Department of Medicine, University of Colorado Denver, Aurora, Colorado.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Eckel
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Aurora, Colorado.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Cramer
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D004852:Epoxy Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology; D007783:Lactones / Q000008:administration & dosage / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D008660:Metabolism; D051379:Mice; D008819:Mice, Nude; D000077403:Orlistat; D010084:Oxidation-Reduction / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011897:Random Allocation; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D007004:Hypoglycemic Agents; D007783:Lactones; D000077403:Orlistat; D002334:Carnitine O-Palmitoyltransferase; C054207:etomoxir