Interplay of reactive oxygen species, intracellular Ca2+ and mitochondrial homeostasis in the apoptosis of prostate cancer cells by deoxypodophyllotoxin
Interplay of reactive oxygen species, intracellular Ca2+ and mitochondrial homeostasis in the apoptosis of prostate cancer cells by deoxypodophyllotoxin
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DOI：
10.1002/jcb.24455
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发表时间：
2013-05-01
影响因子：
4
通讯作者：
Ahn, Soon-Cheol
中科院分区：
文献类型：
--
作者：
Kim, Kwang-Youn;Cho, Hyo-Jin;Ahn, Soon-Cheol
复发性前列腺癌的有限治疗选择和对常规化疗药物的最终抗性激发了人们对寻找天然产物来源的新抗肿瘤剂的持续兴趣。我们以前报道过脱氧鬼臼毒素（DPT）对人前列腺癌细胞的抗增殖活性。使用PC-3细胞模型的人前列腺癌，本研究表明，DPT诱导凋亡通过caspase-3依赖的途径，激活由于线粒体功能失调。DPT处理后细胞内活性氧（ROS）增加，CaI ~（2+）峰升高，线粒体膜电位（MMP，m）升高，Bax蛋白移位至线粒体，细胞色素c释放至胞浆。这导致半胱天冬酶-3活化，其反过来诱导细胞凋亡。抗氧化剂N-乙酰半胱氨酸（NAC）抑制了细胞内ROS的积累、MMP和Ca 2+峰，而钙离子螯合剂BAPTA抑制了Ca 2+超载和MMP，但不影响ROS的增加，表明ROS的产生先于Ca 2+的流出。这表明ROS和Cai 2+信号传导通过Cai 2+依赖性和/或非依赖性机制在增加的MMP中起作用，因为M升高被NAC和BAPTA逆转。这项研究提供了第一个证据参与ROS和Ca 2+激活的信号在线粒体稳态的破坏和优先的ROS生产失败的Ca 2+流量稳态。J.细胞。114：11241134，2013. (c)2012 Wiley Periodicals，Inc.
The limited treatment option for recurrent prostate cancer and the eventual resistance to conventional chemotherapy drugs has fueled continued interest in finding new anti-neoplastic agents of natural product origin. We previously reported anti-proliferative activity of deoxypodophyllotoxin (DPT) on human prostate cancer cells. Using the PC-3 cell model of human prostate cancer, the present study reveals that DPT induced apoptosis via a caspase-3-dependent pathway that is activated due to dysregulated mitochondrial function. DPT-treated cells showed accumulation of the reactive oxygen species (ROS), intracellular Cai2+ surge, increased mitochondrial membrane potential (MMP, m), Bax protein translocation to mitochondria and cytochrome c release to the cytoplasm. This resulted in caspase-3 activation, which in turn induced apoptosis. The antioxidant N-acetylcysteine (NAC) reduced ROS accumulation, MMP and Cai2+ surge, on the other hand the Ca2+ chelator BAPTA inhibited the Cai2+ overload and MMP without affecting the increase of ROS, indicating that the generation of ROS occurred prior to Ca2+ flux. This suggested that both ROS and Cai2+ signaling play roles in the increased MMP via Cai2+-dependent and/or -independent mechanisms, since m elevation was reversed by NAC and BAPTA. This study provides the first evidence for the involvement of both ROS- and Cai2+-activated signals in the disruption of mitochondrial homeostasis and the precedence of ROS production over the failure of Ca2+ flux homeostasis. J. Cell. Biochem. 114: 11241134, 2013. (c) 2012 Wiley Periodicals, Inc.