ANTINEOPLASTIC AND PROTEOMIC SIGNATURE OF SIMVASTATIN TREATED CD44+/ CD24- TRIPLE NEGATIVE BREAST CANCER STEM -LIKE CELLS

Pharmaceutical Science-Pharmacology

Abstract

Simvastatin, a potent HMG CoA reductase inhibitor is gaining significant importance in targeting cancer stem cells. Despites its effects in reducing the expression of CSC surface markers and sphere forming ability in cancer stem cells their molecular mechanism remains poorly understood.In this study we employed label free  quantitative  proteomic  profiling  using  mass  tandem  spectroscopy  to  corroborate  the    effect  of Simvastatin  on the cell proliferation, mammosphere formation  and its apoptotic effect on CD44+/CD24- Breast Cancer Stem Cells (BCSCs).Simvastatin induces inhibition of cell proliferation in CD44+  CD24- BCSCs. Half inhibitory concentration IC50 was found to be 5 µg/ml. Further Simvastatin induces apoptosis in BCSCs stained with Nexin reagent. Furthermore Simvastatin treatment for 48 hrs with various concentrations significantly inhibited the growth of 6 days old mammospheres in a dose dependent manner. In label free quantitative proteomic profiling of Simvastatin treated and untreated BCSCs, 99 differentially expressed proteins were identified of which, 48 were upregulated and  51 were down regulated. Gene ontology  and  KEGG  pathway  enrichment  analysis  exposed  18  potential  pathways  associated  with Simvastatin treatment. These identified pathways were shown to be related with carcinogenesis, tumor progression, metastasis, focal adhesion and metabolic effects in cancer cells. Among the down regulated proteins Vinculin, Heat shock protein beta-1(HSPB1) was significantly down regulated.Our study reveals that Simvastatin potentially targets BCSCs and their regulatory pathways. Further our proteomics profiling implies the better use of existing drugs and new targets in cancer therapeutics.