Profiling Bis(monoacylglycero)phosphate Lipids in Cancer Cell Lysosomes as Therapeutic Targets

Abstract

BackgroundTumor resistance to apoptosis underlies the clinical failure of conventional chemotherapeutics and commonly employed molecularly targeted drugs. Cancer cells frequently activate survival pathways to evade destruction by apoptosis‐inducing therapies and persist following treatment to seed tumor recurrence and metastatic outgrowth. Lysosomal cell death is an alternative death pathway that triggers non‐apoptotic mechanisms. The lysosome, a major degradative component of eukaryotic cells, is altered by oncogenic transformation. Key to the function and stability of lysosome‐associated enzymes are bis(monoacylglycero)‐phosphate lipids (BMP). BMPs are negatively charged and highly enriched in the internal lysosome membrane. Untargeted analytical methods for the measurement of BMPs and in silico libraries to support the discovery of new BMP species are currently lacking.MethodWe present here an expanded BMP library to include over 1800 BMP species in both positive and negative ESI modes. We have chromatographic separation of BMP from isobaric species, and have used this method to profile cancerous and non‐cancerous immortalized cell lines. Lipidomic analysis was performed using Waters Acquity UPLC CSH C18 (100 mm length × 2.1 mm id; 1.7 μm) column coupled to a Thermo Scientific Q‐Exactive HF mass spectrometer. Data processing was done using MS‐DIAL software and in‐silico structure predictions were done using MS‐FINDER.ResultsIn breast cancer cells (Met‐1), we found that all BMP species measured were significantly less abundant relative to non‐transformed mammary epithelial cells (nMUMG), (n = 10). As BMPs are key to lysosome stability, we hypothesize the dramatic loss of BMPs observed in transformed cells renders cancer‐associated lysosomes unstable. Therefore, targeting BMPs might represent an effective therapeutic strategy for selective cancer cell destruction.Support or Funding InformationThis work was funded by NIH U24 DK097154.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.