Unité Inserm U1234/Université de Rouen/IRIB, Faculté de Médecine et Pharmacie, Rouen Cedex, 76183, France.
Service Anatomie et Cytologie pathologiques, Centre Henri Becquerel de Lutte Contre le Cancer (CLCC) de Normandie, Rouen Cedex 1, 76038, France.
Oncogene. 2018 Sep;37(36):4979-4993. doi: 10.1038/s41388-018-0329-6. Epub 2018 May 23.
Recent studies have suggested that the lipid-lowering agent simvastatin holds great promise as a cancer therapeutic; it inhibits the growth of multiple tumors, including triple-negative breast cancer. Doxorubicin- and simvastatin-induced cytotoxicity has been associated with the modulation of Ca signaling, but the underlying mechanisms remain incompletely understood. Here we identify how Ca signaling regulates the breast tumor cell response to doxorubicin and simvastatin. These two drugs inhibit cell survival while increasing apoptosis in two human breast cancer cell lines and five primary breast tumor specimens through the modulation of Ca signaling. Signal transduction and functional studies revealed that both simvastatin and doxorubicin trigger persistent cytosolic Ca release, thereby stimulating the proapoptotic BIM pathway and mitochondrial Ca overload, which are responsible for metabolic dysfunction and apoptosis induction. Simvastatin and doxorubicin suppress the prosurvival ERK1/2 pathway in a Ca-independent and Ca-dependent manner, respectively. In addition, reduction of the Ca signal by chelation or pharmacological inhibition significantly prevents drug-mediated anticancer signaling. Unexpectedly, a scratch-wound assay indicated that these two drugs induce rapid cell migration, while inhibiting cell invasion and colony formation in a Ca-dependent manner. Further, the in vivo data for MDA-MB-231 xenografts demonstrate that upon chelation of Ca, the ability of both drugs to reduce the tumor burden was significantly reduced via caspase-3 deactivation. Our results establish a calcium-based mechanism as crucial for executing the cell death process triggered by simvastatin and doxorubicin, and suggest that combining simvastatin with doxorubicin may be an effective regimen for the treatment of breast cancer.
最近的研究表明，降脂药物辛伐他汀作为一种癌症治疗药物具有巨大的潜力；它可以抑制多种肿瘤的生长，包括三阴性乳腺癌。多柔比星和辛伐他汀诱导的细胞毒性与钙信号的调节有关，但潜在的机制仍不完全清楚。在这里，我们确定了钙信号如何调节乳腺癌细胞对多柔比星和辛伐他汀的反应。这两种药物通过调节钙信号，抑制两种人乳腺癌细胞系和五种原发性乳腺癌标本中的细胞存活，同时增加细胞凋亡。信号转导和功能研究表明，辛伐他汀和多柔比星都触发持续的细胞质 Ca 释放，从而刺激促凋亡 BIM 途径和线粒体 Ca 超载，这是导致代谢功能障碍和凋亡诱导的原因。辛伐他汀和多柔比星分别以 Ca 非依赖性和 Ca 依赖性方式抑制促生存 ERK1/2 途径。此外，通过螯合或药理学抑制来减少钙信号显著阻止了药物介导的抗癌信号。出乎意料的是，划痕试验表明，这两种药物以 Ca 依赖性方式诱导快速细胞迁移，同时抑制细胞侵袭和集落形成。此外，MDA-MB-231 异种移植的体内数据表明，通过 Ca 螯合，两种药物降低肿瘤负担的能力通过 caspase-3 失活而显著降低。我们的结果确立了钙基机制对于执行辛伐他汀和多柔比星触发的细胞死亡过程至关重要，并表明辛伐他汀与多柔比星联合使用可能是治疗乳腺癌的有效方案。
