Calcium-mediated activation of PI3K and p53 leads to apoptosis in thyroid carcinoma cells
Calcium-mediated activation of PI3K and p53 leads to apoptosis in thyroid carcinoma cells
复制标题
DOI：
10.1007/s00018-007-7107-x
复制
发表时间：
2007-06-01
影响因子：
8
通讯作者：
van Hasselt, C. A.
中科院分区：
文献类型：
--
作者：
Liu, Z.-M.;Chen, G. G.;van Hasselt, C. A.
镉诱导甲状腺癌细胞(FRO)细胞死亡的分子机制尚不清楚。我们证明了镉诱导的FRO细胞的凋亡具有浓度和时间依赖性。镉引起细胞内钙离子迅速升高，并诱导Akt、P53、JNK、ERK和p38的磷酸化。抑制PI3K/Akt可减弱镉诱导的细胞凋亡，而抑制JNK抑制剂ERK或p38则加重镉诱导的细胞凋亡，表明PI3K/Akt的激活是镉诱导的促凋亡信号，而应激激活的蛋白激酶JNK、ERK和p38的激活则作为生存信号对抗镉诱导的细胞凋亡。钙离子反应的缓冲减轻了线粒体的损伤，恢复了镉激活的Akt、P53、JNK、ERK和p38，从而阻断了细胞的凋亡。这些结果表明，镉诱导FRO细胞凋亡的机制是细胞内钙离子迅速升高，随后钙离子介导的PI3K/Akt激活和线粒体损伤。
The molecular mechanism responsible for cadmium-induced cell death in thyroid cancer cells (FRO) is unknown. We demonstrated that apoptosis of FRO cells induced by cadmium was concentration and time dependent. Cadmium caused the rapid elevation of intracellular calcium and induced phosphorylation of Akt, p53, JNK, ERK and p38. Inhibition of PI3K/Akt attenuated the cadmium-induced apoptosis, but the inhibition of JNK inhibitor, ERK or p38 aggravated it, indicating that activation of PI3K/Akt was a pro-apoptosis signal in response to cadmium treatment, whereas the activation of stress-activated protein kinase JNK, ERK and p38 functioned as survival signals to counteract the cadmium-induced apoptosis. Buffering of the calcium response attenuated mitochondrial impairment, recovered the cadmium-activated Akt, p53, JNK, ERK and p38, and subsequently blocked the apoptosis. These results suggested that apoptosis induced by cadmium in FRO cells was initiated by the rapid elevation of intracellular calcium, followed by calcium-mediated activation of PI3K/Akt and mitochondrial impairment.