title: Fluvastatin mediated breast cancer cell death: a proteomic approach to identify differentially regulated proteins in MDA-MB-231 cells.
abstract: Statins are increasingly being recognized as anti-cancer agents against various cancers including breast cancer. To understand the molecular pathways targeted by fluvastatin and its differential sensitivity against metastatic breast cancer cells, we analyzed protein alterations in MDA-MB-231 cells treated with fluvastatin using 2-DE in combination with LC-MS/MS. Results revealed dys-regulation of 39 protein spots corresponding to 35 different proteins. To determine the relevance of altered protein profiles with breast cancer cell death, we mapped these proteins to major pathways involved in the regulation of cell-to-cell signaling and interaction, cell cycle, Rho GDI and proteasomal pathways using IPA analysis. Highly interconnected sub networks showed that vimentin and ERK1/2 proteins play a central role in controlling the expression of altered proteins. Fluvastatin treatment caused proteolysis of vimentin, a marker of epithelial to mesenchymal transition. This effect of fluvastatin was reversed in the presence of mevalonate, a downstream product of HMG-CoA and caspase-3 inhibitor. Interestingly, fluvastatin neither caused an appreciable cell death nor did modulate vimentin expression in normal mammary epithelial cells. In conclusion, fluvastatin alters levels of cytoskeletal proteins, primarily targeting vimentin through increased caspase-3- mediated proteolysis, thereby suggesting a role for vimentin in statin-induced breast cancer cell death.
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.
authors.forename: Anantha Koteswararao
authors.initials: AK
authors.lastname: Kanugula
authors.affiliation: Interfacultary Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Vishnu M
authors.initials: VM
authors.lastname: Dhople
authors.affiliation: Interfacultary Institute of Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Völker
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Ummanni
authors.affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.
authors.forename: Srigiridhar
authors.initials: S
authors.lastname: Kotamraju
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D000924:Anticholesteremic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms; D053148:Caspase 3 / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D015180:Electrophoresis, Gel, Two-Dimensional; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005229:Fatty Acids, Monounsaturated / Q000633:toxicity*; D005260:Female; D000077340:Fluvastatin; D006801:Humans; D007211:Indoles / Q000633:toxicity*; D053858:Metabolic Networks and Pathways; D008798:Mevalonic Acid / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D020543:Proteome / Q000032:analysis*; D053719:Tandem Mass Spectrometry; D014746:Vimentin / Q000378:metabolism
chemical_list: D000214:Acyl Coenzyme A; D000924:Anticholesteremic Agents; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D020543:Proteome; D014746:Vimentin; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; D000077340:Fluvastatin; D019950:Mitogen-Activated Protein Kinase 1; D053148:Caspase 3; D008798:Mevalonic Acid