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Targeting Fatty Acid Oxidation to Promote Anoikis and Inhibit Ovarian Cancer Progression 2 3 4 Brandon T

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Targeting Fatty Acid Oxidation to Promote Anoikis and Inhibit Ovarian Cancer Progression 2 3 4 Brandon T Author Manuscript Published OnlineFirst on March 20, 2020; DOI: 10.1158/1541-7786.MCR-19-1057 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Targeting fatty acid oxidation to promote anoikis and inhibit ovarian cancer progression 2 3 4 Brandon T. Sawyer1, Lubna Qamar2, Tomomi M. Yamamoto2, Alexandra McMellen2, Zachary L. 5 Watson2, Jennifer K. Richer4, Kian Behbakht1, Isabel R. Schlaepfer#3, Benjamin G. Bitler#1,2 6 7 1Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of 8 Colorado School of Medicine, Aurora, CO, USA 9 2Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of 10 Colorado School of Medicine, Aurora, CO, USA 11 3Division of Medical Oncology, Department of Medicine, University of Colorado School of 12 Medicine, Aurora, CO, USA 13 4Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA 14 15 Running Title: FAO contributes to ovarian cancer dissemination 16 17 # Corresponding Authors: 18 19 Benjamin G. Bitler 20 Department of Obstetrics and Gynecology 21 University of Colorado Anschutz Medical Campus 22 12700 E. 19th Ave 23 MS 8613 24 Aurora, CO 80045 25 Phone: 303-724-0574 26 [email protected] 27 28 Isabel Schlaepfer 29 Department of Medical Oncology 30 University of Colorado Anschutz Medical Campus 31 12900 E. 19th Ave 32 MS 8117 33 Aurora, CO 80045 34 Phone: 303-724-4430 35 [email protected] 36 37 38 The authors declare no potential conflicts of interest. 39 40 Keywords: Ovarian cancer, Carnitine Palmitoyltransferase 1A, fatty acid beta oxidation, anoikis 41 resistance 42 43 Word Count: 5,535 44 45 Number of tables/figures: 4 figures 1 Downloaded from mcr.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 20, 2020; DOI: 10.1158/1541-7786.MCR-19-1057 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 46 Abstract 47 Epithelial-derived high-grade serous ovarian cancer (HGSOC) is the deadliest 48 gynecologic malignancy. Roughly 80% of patients are diagnosed with late-stage disease, which 49 is defined by wide-spread cancer dissemination throughout the pelvic and peritoneal cavities. 50 HGSOC dissemination is dependent on tumor cells acquiring the ability to resist anoikis 51 (apoptosis triggered by cell detachment). Epithelial cell detachment from the underlying 52 basement membrane or extracellular matrix leads to cellular stress, including nutrient- 53 deprivation. In this report, we examined the contribution of fatty acid oxidation (FAO) in 54 supporting anoikis resistance. We examined expression Carnitine Palmitoyltransferase 1A 55 (CPT1A) in a panel of HGSOC cell lines cultured in adherent and suspension conditions. With 56 CPT1A knockdown cells, we evaluated anoikis by caspase 3/7 activity, cleaved caspase 3 57 immunofluorescence, flow cytometry, and colony formation. We assessed CPT1A-dependent 58 mitochondrial activity and tested the effect of exogenous oleic acid on anoikis and mitochondrial 59 activity. In a patient-derived xenograft model, we administered etomoxir, an FAO inhibitor, 60 and/or platinum-based chemotherapy. CPT1A is overexpressed in HGSOC, correlates with poor 61 overall survival, and is upregulated in HGSOC cells cultured in suspension. CPT1A knockdown 62 promoted anoikis and reduced viability of cells cultured in suspension. HGSOC cells in 63 suspension culture are dependent on CPT1A for mitochondrial activity. In a patient-derived 64 xenograft model of HGSOC, etomoxir, significantly inhibited tumor progression. 65 66 Implications: Targeting FAO in HGSOC to promote anoikis and attenuate dissemination is a 67 potential approach to promote a more durable anti-tumor response and improve patient 68 outcomes. 69 70 (Word count - 238) 2 Downloaded from mcr.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 20, 2020; DOI: 10.1158/1541-7786.MCR-19-1057 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 71 Introduction 72 Epithelial ovarian cancer (EOC) is the deadliest gynecologic malignancy and accounts for over 73 220,000 deaths annually worldwide [1]. HGSOC is the most prevalent EOC subtype, carries the 74 highest mortality rate of all gynecologic malignancies, and the overall survival rate at the time of 75 diagnosis is roughly 40% (1,2). This results from most patients presenting with late stage 76 disease (Stage III or IV) after cancer has disseminated throughout the abdomen and pelvis. The 77 current standard of care treatment consists of a combination of surgery and platinum-based 78 chemotherapy (2,3). Unfortunately, most patients develop recurrent, therapy resistant disease 79 (2,4). 80 81 HGSOC does not follow classical circulatory and lymphatic dissemination modes of other solid 82 tumors, like breast and endometrial cancers. In contrast, HGSOC originates from precursor 83 lesions called serous intraepithelial carcinoma (STIC) at the distal fimbriated end of the fallopian 84 tube (1,5). STIC dissociate from the extracellular matrix (ECM) and directly disseminate to 85 distant sites within the peritoneal cavity. In normal epithelial cells, loss of attachment to the 86 extracellular matrix (ECM) leads to anoikis (anchorage-independent cell death). Thus, HGSOC 87 dissemination is dependent on tumor cells acquiring the ability to resist anoikis and survive long 88 enough to attach to metastatic sites in the peritoneal cavity or survive in ascites. Metabolic 89 characterization of HGSOC cell lines revealed that cells with a high respiration rate resisted 90 anoikis more effectively (6). HGSOC predominantly migrates to fat-rich distant tissues, such as 91 the omentum. Previous studies report that dissemination to the omentum is partially driven by 92 the nutrient microenvironment (2,7), highlighting a potential shift in the metabolic demands of 93 disseminating HGSOC cells. 94 95 Recent research identified fatty acid -oxidation (FAO) as an essential source of metabolites 96 (e.g., NADH, FADH2, and ATP) fueling cancer growth [reviewed in (8) ]. Activation of FAO 3 Downloaded from mcr.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 20, 2020; DOI: 10.1158/1541-7786.MCR-19-1057 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 97 protects cancer cells against environmental stresses, such as glucose deprivation and hypoxia 98 (9). The rate-limiting step of FAO is the membrane transport of long-chain acyl-CoA from the 99 cytoplasm to the inner mitochondrial matrix across the inner mitochondria by the carnitine 100 palmitoyltransferase system (CPT). The CPT system consists of three components: CPT1, 101 CPT2, and carnitine acylcarnitine translocase (CACT). CPT1 is located on the outer 102 mitochondrial membrane and is responsible for converting acyl-CoA into acylcarnitine. 103 Acylcarnitine is shuttled across the inner mitochondrial membrane by CACT, where it is then 104 converted back to acyl-CoA, ready for β-oxidation and energy substrate generation. Importantly, 105 CPT1 is the rate-limiting step of FAO, and due to its metabolic importance, it is of interest as a 106 possible therapeutic vulnerability. Previous work in HGSOC demonstrated that CPT1A (liver 107 isoform) contributes to anchorage-independent survival, suggesting that pharmacologic CPT1A 108 inhibition could be utilized to inhibit HGSOC progression. 109 110 There are several CPT1 inhibitors developed to inhibit FAO. Etomoxir is a specific, irreversible, 111 and orally available CPT1 inhibitor that is highly effective at inhibiting FAO (10,11). Clinical data 112 for etomoxir exists with the majority of early clinical trials examining the potential benefit in 113 chronic heart failure patients. Most recently, a 2007 multicenter randomized control trial was 114 stopped prematurely due to evidence of hepatotoxicity deemed unacceptable for the study 115 population (12). Importantly, however, the reported liver enzyme elevations in this study are 116 reasonable in the cancer setting. Preclinical in vivo models of prostate and colorectal cancers 117 find etomoxir to have anti-neoplastic properties by reduces tumor progression and inhibiting 118 metastasis (13,14). Until now, an in vivo model examining etomoxir in an ovarian cancer model 119 has not been reported. 120 121 Ultimately, defining the relationship between anoikis resistance and HGSOC dissemination 122 patterns is important and could provide a strong rationale for therapeutic interventions against 4 Downloaded from mcr.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 20, 2020; DOI: 10.1158/1541-7786.MCR-19-1057 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 123 HGSOC. Emerging evidence from our lab and others (7,14-16) suggests that elevated FAO is 124 an important adaptation that allows HGSOC to survive ECM-detachment and resist anoikis. 125 Therefore, in this report, we further define the role of FAO and CPT1A in promoting anoikis 126 resistance and demonstrate etomoxir effectively inhibits tumor progression. 5 Downloaded from mcr.aacrjournals.org
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