title: Statin-induced inhibition of breast cancer proliferation and invasion involves attenuation of iron transport: intermediacy of nitric oxide and antioxidant defence mechanisms.
abstract: Accumulating evidence from in vitro, in vivo, clinical and epidemiological studies shows promising results for the use of statins against many cancers including breast carcinoma. However, the molecular mechanisms responsible for the anti-proliferative and anti-invasive properties of statins still remain elusive. In this study, we investigated the involvement of nitric oxide, iron homeostasis and antioxidant defence mechanisms in mediating the anti-proliferative and anti-invasive properties of hydrophobic statins in MDA-MB-231, MDA-MB-453 and BT-549 metastatic triple negative breast cancer cells. Fluvastatin and simvastatin significantly increased cytotoxicity which was reversed with mevalonate. Interestingly, fluvastatin downregulated transferrin receptor (TfR1), with a concomitant depletion of intracellular iron levels in these cells. Statin-induced effects were mimicked by geranylgeranyl transferase inhibitor (GGTI-298) but not farnesyl transferase inhibitor (FTI-277). Further, it was observed that TfR1 downregulation is mediated by increased nitric oxide levels via inducible nitric oxide synthase (iNOS) expression. NOS inhibitors (asymmetric dimethylarginine and 1400W) counteracted and sepiapterin, a precursor of tetrahydrobiopterin, exacerbated statin-induced depletion of intracellular iron levels. Notably, fluvastatin increased manganese superoxide dismutase (by repressing the transcription factor DNA damage-binding protein 2), catalase and glutathione which, in turn, diminished H2 O2 levels. Fluvastatin-induced downregulation of TfR1, matrix metalloproteinase-2, -9 and inhibition of invasion were reversed in the presence of aminotriazole, a specific inhibitor of catalase. Finally, we conclude that fluvastatin, by altering iron homeostasis, nitric oxide generation and antioxidant defence mechanisms, induces triple negative breast cancer cell death.
authors: Centre for Chemical Biology, CSIR Indian Institute of Chemical Technology, Hyderabad, India.
authors: Anantha Koteswararao
authors: AK
authors: Kanugula
authors: Paradesi Naidu
authors: PN
authors: Gollavilli
authors: Sathish Babu
authors: SB
authors: Vasamsetti
authors: Santosh
authors: S
authors: Karnewar
authors: Raja
authors: R
authors: Gopoju
authors: Ramesh
authors: R
authors: Ummanni
authors: Srigiridhar
authors: S
authors: Kotamraju
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005260:Female; D000077340:Fluvastatin; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism*; D008798:Mevalonic Acid / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D064726:Triple Negative Breast Neoplasms
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; D000975:Antioxidants; C068126:CD71 antigen; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D011990:Receptors, Transferrin; D009569:Nitric Oxide; D000077340:Fluvastatin; D019821:Simvastatin; D006861:Hydrogen Peroxide; D007501:Iron; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D013482:Superoxide Dismutase; D008798:Mevalonic Acid
keywords: H2O2; MnSOD; breast cancer; fluvastatin; invasion; iron; nitric oxide; transferrin receptor