4-Cholesten-3-one Modified the Lipidome of MDA-MB-231 Cells and Potentiated the Effect of Docetaxel.

Lipids are essential for energy production, signaling, and membrane formation, hence increased lipid metabolism may lead to cancer growth. 4-cholesten-3-one (4Cone), a sterol metabolite, has various biological activities, including the inhibition of cancer growth. This study examined whether 4Cone could change the lipid profile of triple-negative breast cancer cells (MDA-MB-231) and whether in combination with the anti-cancer chemotherapy docetaxel (TXT) could further reduce cancer aggressiveness. The effect of 4Cone, TXT, or their combination (4Cone/TXT) on migration and proliferation was examined utilizing the wound healing and MTT assays. The expression of the lipogenesis-related enzymes was assessed using RT-qPCR and lipid profile was examined using mass spectrometry. 4Cone and TXT individually reduced cell viability and migration of MDA-MB-231 cancer cells; however, their combination (4Cone/TXT) had a greater impact on both attributes. All treated cells showed markedly decreased levels of the multidrug resistance enzyme PGP as well as the lipogenic enzymes FASN, ACC1, SCD1, HMGCR, and DGAT. Furthermore, lipid fingerprints were markedly different in treated cells compared with the untreated group. 4Cone increased the percentage of sphingomyelin (SM) while it decreased the percentage of ceramide (Cer); 4Cone in conjunction with TXT had the reverse effect. Triglyceride levels were reduced in 4Cone- and 4Cone/TXT-treated cells, but interestingly, they increased in TXT-treated cells. Additionally, treated cancer cells exhibited changes in glycerophospholipid subclasses. 4Cone alone or in combination with TXT alters the lipid profile by reducing a key lipogenic enzyme, resulting in the inhibition of cell proliferation and migration.