Centre for Chemical Biology, CSIR Indian Institute of Chemical Technology, Hyderabad, India.
FEBS J. 2014 Aug;281(16):3719-38. doi: 10.1111/febs.12893. Epub 2014 Jul 30.
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.
越来越多的来自体外、体内、临床和流行病学研究的证据表明，他汀类药物在治疗多种癌症方面具有广阔的前景，包括乳腺癌。然而，他汀类药物具有抗增殖和抗侵袭特性的分子机制仍不清楚。在这项研究中，我们研究了一氧化氮、铁平衡和抗氧化防御机制在介导疏水性他汀类药物在 MDA-MB-231、MDA-MB-453 和 BT-549 转移性三阴性乳腺癌细胞中的抗增殖和抗侵袭特性中的作用。氟伐他汀和辛伐他汀显著增加了细胞毒性，而甲羟戊酸则逆转了这种作用。有趣的是，氟伐他汀下调了转铁蛋白受体（TfR1），同时使这些细胞内的铁水平下降。法尼基转移酶抑制剂（FTI-277）不能模拟，而香叶基转移酶抑制剂（GGTI-298）可以模拟他汀类药物的诱导作用。进一步观察到，TfR1 的下调是通过诱导型一氧化氮合酶（iNOS）表达增加一氧化氮水平介导的。NOS 抑制剂（不对称二甲基精氨酸和 1400W）逆转了他汀类药物诱导的细胞内铁水平下降，而四氢生物蝶呤的前体蝶酰谷氨酸则加剧了这种下降。值得注意的是，氟伐他汀通过抑制转录因子 DNA 损伤结合蛋白 2（repressing transcription factor DNA damage-binding protein 2）来增加锰过氧化物酶（manganese superoxide dismutase）、过氧化氢酶和谷胱甘肽，从而降低了 H2O2 水平。在存在氨基三唑（一种过氧化氢酶的特异性抑制剂）的情况下，氟伐他汀诱导的 TfR1 下调、基质金属蛋白酶-2、-9 的下调和侵袭抑制作用被逆转。最后，我们得出结论，氟伐他汀通过改变铁平衡、一氧化氮生成和抗氧化防御机制，诱导三阴性乳腺癌细胞死亡。
