Acquisition of apoptotic resistance in cadmium-transformed human prostate epithelial cells: Bcl-2 overexpression blocks the activation of JNK signal transduction pathway.
Acquisition of apoptotic resistance in cadmium-transformed human prostate epithelial cells: Bcl-2 overexpression blocks the activation of JNK signal transduction pathway.
复制标题
DOI：
10.1289/ehp.10075
复制
发表时间：
2007-07
影响因子：
10.4
通讯作者：
Waalkes MP
中科院分区：
文献类型：
--
作者：
Qu W;Ke H;Pi J;Broderick D;French JE;Webber MM;Waalkes MP
我们最近发现，镉可以诱导人前列腺上皮细胞系（RWPE-1）的恶性转化，这些镉转化的前列腺上皮（CTPE）细胞获得凋亡抗性与恶性表型同时发生。本研究旨在确定CTPE细胞中获得性凋亡抗性的机制。在连续镉暴露8周后获得的对照和CTPE细胞中评估与细胞凋亡相关的各种分子事件。与对照组相比，CTPE细胞表现出对镉、顺铂或足叶乙甙诱导的凋亡的普遍抵抗。信号调节的丝裂原活化蛋白激酶，细胞外信号调节激酶1和2，c-Jun N-末端激酶（JNK 1和JNK 2），和p38磷酸化的镉浓度依赖性的方式在CTPE和对照细胞。然而，磷酸化JNK 1/2水平和JNK激酶活性在CTPE细胞中要低得多。促凋亡基因Bax在CTPE细胞中表现出较低的转录和蛋白水平，而抗凋亡基因Bcl-2在CTPE细胞中表现出较高的水平。Bcl-2/Bax的比例，在凋亡承诺的关键决定因素，增加超过4倍的CTPE细胞。在Bcl-2转染的PT-67细胞中，磷酸化JNK 1/2水平在致瘤刺激后明显降低，镉或依托泊苷诱导的凋亡与对照相比减少。Bcl-2蛋白BH 4结构域第21位氨基酸的酪氨酸突变为丝氨酸导致JNK 1/2磷酸化抑制和抗凋亡功能的丧失。CTPE细胞在恶性转化过程中对凋亡具有抗性，JNK通路的破坏和Bcl-2过表达在这种抗性中起重要作用。Bcl-2 BH 4结构域是调节JNK磷酸化和抗凋亡功能所必需的。
We have recently shown that cadmium can induce malignant transformation of the human prostate epithelial cell line (RWPE-1) and that these cadmium-transformed prostate epithelial (CTPE) cells acquire apoptotic resistance concurrently with malignant phenotype. The present study was designed to define the mechanism of acquired apoptotic resistance in CTPE cells. Various molecular events associated with apoptosis were assessed in control and CTPE cells that were obtained after 8 weeks of continuous cadmium exposure. Compared with control, CTPE cells showed a generalized resistance to apoptosis induced by cadmium, cisplatin, or etoposide. Signal-regulated mitogen-activated protein kinases, extracellular signal-regulated kinases 1 and 2, c-Jun N-terminal kinases (JNK1 and JNK2), and p38 were phosphorylated in a cadmium concentration-dependent fashion in CTPE and control cells. However, phosphorylated JNK1/2 levels and JNK kinase activity were much lower in CTPE cells. The pro-apoptotic gene Bax showed lower transcript and protein levels, whereas the anti-apoptotic gene Bcl-2 showed higher levels in CTPE cells. The ratio of Bcl-2/Bax, a key determinant in apoptotic commitment, increased more than 4-fold in CTPE cells. In Bcl-2–transfected PT-67 cells, phosphorylated JNK1/2 levels were much lower after apoptogenic stimulus, and apoptosis induced by cadmium or etoposide was reduced compared with control. Mutation of tyrosine to serine at the 21st amino acid of the Bcl-2 protein BH4 domain resulted in a loss both of suppression of JNK1/2 phosphorylation and its anti-apoptotic function. CTPE cells become resistant to apoptosis during malignant transformation, and disruption of the JNK pathway and Bcl-2 overexpression play important roles in this resistance. Bcl-2 BH4 domain is required for modulating JNK phosphorylation and anti-apoptotic function.
登录
查看更多内容
影响因子：
16.2
作者：
Putcha, GV;Le, SY;Johnson, EM
通讯作者：
Johnson, EM
影响因子：
3.8
作者：
Qu, W;Kasprzak, KS;Waalkes, MP
通讯作者：
Waalkes, MP
DOI：
10.1073/pnas.95.9.5045
发表时间：
1998-04-28
影响因子：
11.1
作者：
Mohr, S;McCormick, TS;Lapetina, EG
通讯作者：
Lapetina, EG
Jun-N末端激酶在Anoikis中的作用； Bcl-2和CRMA抑制。
影响因子：
7.8
作者：
Frisch, SM;Vuori, K;Kelaita, D;Sicks, S
通讯作者：
Sicks, S
影响因子：
4.7
作者：
Qu, W;Bortner, CD;Waalkes, MP
通讯作者：
Waalkes, MP