Submission
| Title: | Ferroptosis Regulation by Fatty Acid Synthase-Derived Lipid Droplets in Model of Breast Cancer Metastasis |
| Presenter: | Chaylen Andolino |
| Institution: | Purdue University |
| Authors: | Chaylen Andolino1, Kimberly K. Buhman1, Michael F. Coleman2, Stephen D. Hursting2, Marjorie Layosa1, Michael K. Wendt3, Dorothy Teegarden1 1Department of Nutrition Science, Purdue University, West Lafayette, IN 2Department of Nutrition, University of North Carolina, Chapel Hill, NC 3Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN |
Abstract
| Background/Significance/Rationale: | Dysregulated metabolism, including lipid droplet (LD) accumulation, is associated with breast cancer progression. Given that breast cancer metastasis accounts for majority of patient deaths, we sought to identify novel mechanisms by which LDs may promote metastasis. |
| Methods: | Whole cell lysates (WCLs) and LDs from vehicle-treated and FASN-inhibited (3d, 20 µM TVB-3166) human metastatic MCF10CA1a cells were prepared for untargeted proteomics analysis. Tryptic/Lys-C peptides were analyzed by reverse-phase LC-ESI-MS/MS by data-dependent acquisition. |
| Results/Findings: | Over 60% of the total proteins identified from LD fractions were unique to vehicle-treated cells (1,571), whereas only 19 proteins were unique to LDs from FASN-inhibited cells. Proteins unique to LDs from vehicle-treated cells include those known to reduce cancer cell survival and progression, such as cadherin-binding and cell cycle regulation proteins. The association of these proteins to LDs might prevent them from functioning at their normal sites of action. Pro-ferroptotic proteins were more abundant on LDs of the more migratory cells, despite similar levels between WCLs, suggesting that the machinery for ferroptosis may be mislocalized in TAG-rich cells, thereby protecting them from ferroptosis. Indeed, FASN-inhibited cells had nearly 30% more intracellular iron compared to the vehicle-treated cells, indicating higher levels of ferroptotic stress. Vehicle-treated cells were 25% more readily rescued by N-acetylcysteine from ferroptosis induced by erastin than were FASN-inhibited cells, despite comparable sensitivity to erastin. |
| Conclusions/Discussion: | These findings indicate that FASN-derived LDs in metastatic cells may aid in protecting against ferroptosis to promote breast cancer progression. |
| Translational/Human Health Impact: | Identifying a role of FASN-derived LD accumulation in modulating protein localization involved in the novel cell death mechanism of ferroptosis in metastatic breast cancer cells provides leverage to further explore the clinical relevance of inhibiting FA synthesis of lipid-rich breast cancers in an effort to induce cancer-specific ferroptosis lethality. |
