Role of mitochondria and caspases in vitamin D-mediated apoptosis of MCF-7 breast cancer cells
Role of mitochondria and caspases in vitamin D-mediated apoptosis of MCF-7 breast cancer cells
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DOI：
10.1074/jbc.m006876200
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发表时间：
2001-03-23
影响因子：
4.8
通讯作者：
Welsh, J
中科院分区：
文献类型：
--
作者：
Narvaez, CJ;Welsh, J
维生素D-3化合物目前正在人类乳腺癌的临床试验中，为这种疾病的抗激素治疗提供了一种替代方法。1 α，25-二羟基维生素D-3 (1 α,25（OH)(2)D-3）是维生素D-3的活性形式，可诱导乳腺癌细胞和肿瘤细胞凋亡，但其潜在机制尚不清楚。在这些研究中，我们重点研究了caspase激活和线粒体破坏在1 α，25(OH)(2) d -3介导的乳腺癌细胞（MCF-7）体外凋亡中的作用。比较1 α，25(OH)(2)D-3与肿瘤坏死因子α对MCF-7细胞的作用，肿瘤坏死因子α通过caspase依赖途径诱导细胞凋亡。我们的主要发现是，1 α,25(OH)(2)D-3通过破坏线粒体功能诱导MCF-7细胞凋亡，这与Bax易位到线粒体、细胞色素c释放和活性氧的产生有关。此外，研究人员发现，在1 α，25(OH)(2)D-3对MCF-7细胞克隆进行抗1 α，25(OH)(2)D-3介导的凋亡处理后，Bax易位和线粒体破坏不会发生。1 α,25(OH)(2)D-3的这些线粒体效应不需要半胱天冬酶激活，因为它们不会被细胞渗透性半胱天冬酶抑制剂z- val - ala - asp -氟甲基酮阻断。尽管caspase抑制阻断了线粒体下游1 α，25(OH)(2) d -3介导的事件，如聚（adp核糖）聚合酶裂解、磷脂酰丝氨酸的外部显示和DNA断裂，但MCF-7细胞在z- vala - ala - asp -氟甲基酮存在下仍然执行凋亡，这表明对1 α，25(OH)(2) d -3介导的细胞死亡的承诺是caspase独立的。
Vitamin D-3 compounds are currently in clinical trials for human breast cancer and offer an alternative approach to anti-hormonal therapies for this disease. 1 alpha ,25-Dihydroxyvitamin D-3 (1 alpha ,25(OH)(2)D-3), the active form of vitamin D-3, induces apoptosis in breast cancer cells and tumors, but the underlying mechanisms are poorly characterized. In these studies, we focused on the role of caspase activation and mitochondrial disruption in 1 alpha ,25(OH)(2)D-3-mediated apoptosis in breast cancer cells (MCF-7) in vitro. The effect of 1 alpha ,25(OH)(2)D-3 on MCF-7 cells was compared with that of tumor necrosis factor alpha, which induces apoptosis via a caspase-dependent pathway. Our major findings are that 1 alpha ,25(OH)(2)D-3 induces apoptosis in MCF-7 cells by disruption of mitochondrial function, which is associated with Bax translocation to mitochondria, cytochrome c release, and production of reactive oxygen species. Moreover, we show that Bax translocation and mitochondrial disruption do not occur after 1 alpha ,25(OH)(2)D-3 treatment of a MCF-7 cell clone selected for resistance to 1 alpha ,25(OH)(2)D-3-mediated apoptosis. These mitochondrial effects of 1 alpha ,25(OH)(2)D-3 do not require caspase activation, since they are not blocked by the cell-permeable caspase inhibitor z-Val-Ala-Asp-fluoromethylketone. Although caspase inhibition blocks 1 alpha ,25(OH)(2)D-3-mediated events downstream of mitochondria such as poly(ADP-ribose) polymerase cleavage, external display of phosphatidylserine, and DNA fragmentation, MCF-7 cells still execute apoptosis in the presence of z-Val-Ala-Asp-fluoromethylketone, indicating that the commitment to 1 alpha ,25(OH)(2)D-3-mediated cell death is caspase-independent.