4.5 Article

Targeting Fatty Acid Oxidation to Promote Anoikis and Inhibit Ovarian Cancer Progression

Journal

MOLECULAR CANCER RESEARCH
Volume 18, Issue 7, Pages 1088-1098

Publisher

AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-19-1057

Keywords

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Funding

  1. NIH [R00CA194318]
  2. American Cancer Society [ACS-IRG, 16-184-56, RSG-16-256-01-TBE, RSG-19-129-01-DDC]
  3. Cancer League of Colorado [AWD-193286]
  4. University of Colorado Cancer Center Support Grant [P30CA046934]
  5. Department of Defense OCRP [OC170228]

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Epithelial-derived high-grade serous ovarian cancer (HGSOC) is the deadliest gynecologic malignancy. Roughly 80% of patients are diagnosed with late-stage disease, which is defined by widespread cancer dissemination throughout the pelvic and peritoneal cavities. HGSOC dissemination is dependent on tumor cells acquiring the ability to resist anoikis (apoptosis triggered by cell detachment). Epithelial cell detachment from the underlying basement membrane or extracellular matrix leads to cellular stress, including nutrient deprivation. In this report, we examined the contribution of fatty acid oxidation (FAO) in supporting anoikis resistance. We examined expression Carnitine Palmitoyl-transferase 1A (CPT1A) in a panel of HGSOC cell lines cultured in adherent and suspension conditions. With CPT1A knockdown cells, we evaluated anoikis by caspase 3/7 activity, cleaved caspase 3 immunofluorescence, flow cytometry, and colony formation. We assessed CPT1A-dependent mitochondrial activity and tested the effect of exogenous oleic acid on anoikis and mitochondrial activity. In a patient-derived xenograft model, we administered etomoxir, an FAO inhibitor, and/or platinum-based chemotherapy. CPT1A is overexpressed in HGSOC, correlates with poor overall survival, and is upregulated in HGSOC cells cultured in suspension. CPT1A knockdown promoted anoikis and reduced viability of cells cultured in suspension. HGSOC cells in suspension culture are dependent on CPT1A for mitochondrial activity. In a patient-derived xenograft model of HGSOC, etomoxir significantly inhibited tumor progression.

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