4-Cholesten-3-one Modified the Lipidome of MDA-MB-231 Cells and Potentiated the Effect of Docetaxel
Sristy Saha1, Mikaël Croyal2,3, Jean-Michel Huvelin1
1Nantes Université, UR2160 ISOMer, Nantes, France.
Background/Aim:
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.
Materials And Methods:
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.
Results:
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.
Conclusion:
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.
Insights
The sterol metabolite 4-cholesten-3-one (4Cone) and docetaxel (TXT) inhibit triple-negative breast cancer cell growth and migration. Their combination significantly alters cancer cell lipid profiles, reducing lipogenic enzymes and impacting cell aggressiveness.
Area of Science:
- Biochemistry
- Cancer Biology
- Lipid Metabolism
Background:
- Lipid metabolism is crucial for cancer cell growth and survival.
- 4-cholesten-3-one (4Cone) is a sterol metabolite with known anti-cancer properties.
- Triple-negative breast cancer (TNBC) exhibits aggressive behavior and requires novel therapeutic strategies.
Purpose of the Study:
- To investigate the effects of 4Cone on the lipid profile of MDA-MB-231 triple-negative breast cancer cells.
- To evaluate the combined efficacy of 4Cone and docetaxel (TXT) in reducing cancer aggressiveness.
- To identify key lipogenic enzymes and lipid species affected by 4Cone and TXT treatment.
Main Methods:
- Cell viability and migration were assessed using MTT and wound healing assays.
- Expression of lipogenesis-related enzymes was quantified via RT-qPCR.
- Lipid profiles were analyzed using mass spectrometry.
Main Results:
- Both 4Cone and TXT reduced MDA-MB-231 cell viability and migration; their combination demonstrated a synergistic effect.
- Treatment with 4Cone and/or TXT significantly downregulated key lipogenic enzymes (FASN, ACC1, SCD1, HMGCR, DGAT) and P-glycoprotein.
- Significant alterations in lipid profiles were observed, including changes in sphingomyelin, ceramide, triglyceride, and glycerophospholipid subclasses.
Conclusions:
- 4Cone, alone or in combination with TXT, effectively inhibits cancer cell proliferation and migration.
- The anti-cancer effects are associated with significant modulation of the cellular lipid profile and downregulation of lipogenic enzymes.
- This study highlights the therapeutic potential of targeting lipid metabolism in triple-negative breast cancer.
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