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.
Highlights
Emerging data suggest that the pleotropic effects of statins (HMG-CoA reductase inhibitors) contribute to their anti neoplastic, anti inflammatory and neuroprotection
Recently we reported that fluvastatin and simvastatin induce triple negative breast cancer (TNBC) cell death by increasing iNOS-dependent nitric oxide levels and dys-regulation of iron homeostasis in MDAMB-231, MDA-MB-453 and BT-549 cells [7]
We investigated the comparative proteome of metastatic MDA-MB-231 breast cancer cells exposed to fluvastatin and control treated cells by 2-D gel electrophoresis (2-DE) for protein separation followed by LC-ESI-MS/MS for protein identification
Summary
Emerging data suggest that the pleotropic effects of statins (HMG-CoA reductase inhibitors) contribute to their anti neoplastic, anti inflammatory and neuroprotection. We have shown that both fluvastatin and simvastatin induce MCF-7 breast cancer cell death by inducing nitric oxide via iNOS and arginase dependent pathways [6]. Recently we reported that fluvastatin and simvastatin induce triple negative breast cancer (TNBC) cell death by increasing iNOS-dependent nitric oxide levels and dys-regulation of iron homeostasis in MDAMB-231, MDA-MB-453 and BT-549 cells [7]. Stable isotope labeling by/with amino acids in cell culture -based proteomic approach in lovastatin-induced human acute promyelocytic leukemia (HL-60) cells quantified 3200 proteins, among which 120 proteins were significantly altered which were mapped to regulating various cellular pathways including inhibition of cholesterol biosynthesis, estrogen receptor signaling, glutamate metabolism and protein ubiquitination [12]
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