Inhibition of collagen XI alpha 1-induced fatty acid oxidation triggers apoptotic cell death in cisplatin-resistant ovarian cancer.

Authors

• Sameera Nallanthighal
• Miran Rada
• James Patrick Heiserman
• Jennifer Cha
• Jessica Sage
• Bo Zhou
• Wei Yang
• Ye Hu
• Chaitali Korgaonkar
• Christina T Hanos Black MD, Lehigh Valley Health NetworkFollow
• Zahra Ashkavand
• Kenneth Norman
• Sandra Orsulic
• Dong-Joo Cheon

Publication/Presentation Date

4-20-2020

Abstract

Collagen type XI alpha 1 (COL11A1) is a novel biomarker associated with cisplatin resistance in ovarian cancer. However, the mechanisms underlying how COL11A1 confers cisplatin resistance in ovarian cancer are poorly understood. We identified that fatty acid β-oxidation (FAO) is upregulated by COL11A1 in ovarian cancer cells and that COL11A1-driven cisplatin resistance can be abrogated by inhibition of FAO. Furthermore, our results demonstrate that COL11A1 also enhances the expression of proteins involved in fatty acid synthesis. Interestingly, COL11A1-induced upregulation of fatty acid synthesis and FAO is modulated by the same signaling molecules. We identified that binding of COL11A1 to its receptors, α1β1 integrin and discoidin domain receptor 2 (DDR2), activates Src-Akt-AMPK signaling to increase the expression of both fatty acid synthesis and oxidation enzymes, although DDR2 seems to be the predominant receptor. Inhibition of fatty acid synthesis downregulates FAO despite the presence of COL11A1, suggesting that fatty acid synthesis might be a driver of FAO in ovarian cancer cells. Taken together, our results suggest that COL11A1 upregulates fatty acid metabolism in ovarian cancer cells in a DDR2-Src-Akt-AMPK dependent manner. Therefore, we propose that blocking FAO might serve as a promising therapeutic target to treat ovarian cancer, particularly cisplatin-resistant recurrent ovarian cancers which typically express high levels of COL11A1.

Volume

11

Issue

4

First Page

258

Last Page

258

ISSN

2041-4889

Published In/Presented At

Nallanthighal, S., Rada, M., Heiserman, J. P., Cha, J., Sage, J., Zhou, B., Yang, W., Hu, Y., Korgaonkar, C., Hanos, C. T., Ashkavand, Z., Norman, K., Orsulic, S., & Cheon, D. J. (2020). Inhibition of collagen XI alpha 1-induced fatty acid oxidation triggers apoptotic cell death in cisplatin-resistant ovarian cancer. Cell death & disease, 11(4), 258. https://doi.org/10.1038/s41419-020-2442-z

Disciplines

Medicine and Health Sciences

PubMedID

32312965

Department(s)

Department of Medicine

Document Type

Article