Abstract
Abstract Ovarian cancer is the most lethal gynecological cancer and affects one in 70 females in the United States during their lifetime. Cisplatin resistance is the major challenge in the treatment of ovarian cancer but the underlying mechanisms are not fully understood. The purpose of this study is to develop novel therapeutic strategies to treat cisplatin-resistant ovarian cancer. We identified collagen type XI alpha 1 (COL11A1) as a novel biomarker associated with cisplatin resistance in ovarian cancer. COL11A1 is highly expressed by cancer-associated fibroblasts adjacent to cancer cells as well as A2780CIS cisplatin-resistant ovarian cancer cell line. Our data show that COL11A1 binds to DDR2 in ovarian cancer cells and inhibits cisplatin-induced apoptosis in ovarian cancer cells. To obtain mechanistic insights underlying COL11A1-driven cisplatin resistance, we performed Tandem Mass Tag proteomic analysis of A2780CIS ovarian cancer cells before and after COL11A1 knockdown. Our proteomics data revealed that mitochondrial fatty acid β-oxidation was the most upregulated pathway by COL11A1 in ovarian cancer cells. Mitochondrial fatty acid β-oxidation is the major pathway that breaks down fatty acids to produce excess ATP and NADPH to support cell survival. Several studies suggested the association of β-oxidation with tumor cell proliferation in various cancers. However, the role of β-oxidation in ovarian cancer chemoresistance is largely unknown. Our results show that COL11A1 enhances the expression of not only fatty acid receptor CD36, but also key enzymes of fatty acid β-oxidation, such as CPT1A, HADHB, ACSL1 and ACAA2. Significantly, COL11A1-mediated overexpression of these proteins was diminished in the presence of shRNA against DDR2.We also confirmed that ovarian cancer cells increase both fatty acid uptake and oxygen consumption rate in response to palmitate in the presence of COL11A1. Importantly, inhibition of fatty acid β-oxidation using shRNA against CPT1A attenuated the function of COL11A1 in cisplatin resistance. Taken together, our results suggest that COL11A1 confers cisplatin resistance by increasing fatty acid β-oxidation in ovarian cancer cells. Our study uncovers fatty acid β-oxidation as a promising therapeutic target to treat cisplatin-resistant ovarian cancer, particularly cisplatin-resistant recurrent ovarian cancers which typically express high levels of COL11A1. Citation Format: Miran Rada, Jennifer Cha, Jessica Sage, Bo Zhou, Wei Yang, Zahra Ashkavand, Kenneth Norman, Sandra Orsulic, Dong-Joo Cheon. Beta-oxidation inhibition as a novel therapy for cisplatin-resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3526.
Published Version
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