Maine Medical Center, Medical Education, Maine Medical Center Research Institute
Multiple Myeloma, Cell Proliferation, Diacylglycerol O-Acyltransferase
Multiple myeloma (MM) is the third most common blood cancer and is defined by the clonal expansion of malignant plasma cells in the bone marrow (BM). MM remains incurable due to the development of resistance to current chemotherapies; therefore, it is paramount to investigate novel treatments and the mechanisms of drug resistance in multiple myeloma cells. Recently, changes in both catabolic and anabolic lipid metabolism have been shown to support the proliferation, migration and the development of drug resistance in breast, prostate, and ovarian cancer. However, the role of lipid metabolism in myeloma cells has been understudied. Given the data in other cancers, we hypothesized that lipid metabolism contributes to myeloma cell proliferation and drug resistance. In order to test the role of global lipid metabolism in MM cell proliferation, we treated human and mouse myeloma cell lines with an inhibitor (Triacsin C, TriC) of acyl CoA synthetase (ACSL), an enzyme critical for both catabolic and anabolic lipid metabolism. Interestingly, TriC treatment severely decreased MM cell proliferation and increased apoptosis in a dose-dependent manner. Motivated to understand the specific mechanism of TriC’s toxicity, we explored the individual contributions of catabolic and anabolic lipid metabolism to myeloma cell proliferation. Here, we report that myeloma cells accumulate lipid droplets, express lipid droplet-related transcripts and can utilize lipid droplets as an energy source. We hypothesized that inhibition of lipid droplet formation would increase cytosolic free fatty acids that could be used to fuel proliferation in myeloma cells. Surprisingly, treatment with inhibitors against the rate-limiting enzymes that are responsible for the formation of lipid droplets did not alter the proliferation of both human and mouse myeloma cell lines. Taken together, our data suggests that global lipid metabolism is critical for myeloma cell proliferation but lipid droplet formation is dispensable in this process. Future directions will explore the role of de novo fatty acid synthesis and catabolic lipid metabolism with respect to myeloma cell proliferation, migration and drug resistance.
Murphy, C S.; Campbell, H; DeMambro, V; Farrell, M; Costas, S; Vary, C; and Reagan, M R., "DGAT Activity is Dispensable for Myeloma Cell Proliferation" (2020). Costas T. Lambrew Research Retreat 2020. 10.