Depletion of intracellular glutathione contributes to JNK-mediated death receptor 5 upregulation and apoptosis induction by the novel synthetic triterpenoid methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me)
Depletion of intracellular glutathione contributes to JNK-mediated death receptor 5 upregulation and apoptosis induction by the novel synthetic triterpenoid methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me)
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DOI：
10.4161/cbt.5.5.2565
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发表时间：
2006-05-01
影响因子：
3.6
通讯作者：
Sun, Shi-Yong
中科院分区：
文献类型：
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作者：
Yue, Ping;Zhou, Zhongmei;Sun, Shi-Yong
新合成的三萜类化合物甲基-2-氰基-3，12-二氧代齐墩果烷-1，9-二烯-28-酸酯（CDDO-Me）诱导人癌细胞凋亡，显示出作为癌症治疗剂的潜力。我们以前证明，CDDO-Me诱导c-Jun N-末端激酶（JNK）介导的DR 5表达和凋亡。该研究揭示了CDDO-Me诱导JNK活化和随后的DR 5上调和凋亡的机制。为了确定CDDO-Me是否通过诱导活性氧（ROS）的产生通过氧化应激激活JNK并诱导DR 5表达和凋亡，我们检查了各种抗氧化剂对JNK激活、DR 5上调和CDDO-Me诱导的凋亡的影响。硫醇类抗氧化剂，包括N-乙酰基-L-半胱氨酸（NAC）、谷胱甘肽（GSH）和二硫苏糖醇（DTT），消除了CDDO-Me诱导的凋亡。相比之下，非硫醇类抗氧化剂，包括丁基羟基茴香醚（BHA），Trolox，甘露醇，和锰（II）四（4-苯甲酸）卟啉氯化物（MnTBAP），未能做到这一点，与维生素C（维生素C）除外。因此，只有巯基抗氧化剂阻断由CDDO-Me诱导的JNK活化。CDDO-Me降低细胞内GSH水平;这种降低仅被巯基抗氧化剂和维生素C消除。然而，CDDO-Me并不促进ROS的产生。这些结果表明，细胞内GSH的耗竭，而不是ROS的产生，有助于CDDO-Me诱导的JNK激活和凋亡，至少在我们的系统中。此外，这些巯基抗氧化剂消除CDDO-Me诱导的DR 5表达，而GSH消耗剂马来酸二乙酯在消耗细胞内GSH的浓度下也上调DR 5表达，表明GSH消耗可导致DR 5上调。总的来说，我们得出结论，CDDO-Me激活JNK途径通过耗尽细胞内GSH，导致DR 5上调和诱导细胞凋亡。
The novel synthetic triterpenoid methyl-2-cyano-3, 12-dioxooleana-1,9-dien-28-oate (CDDO-Me) induces apoptosis in human cancer cells, showing potential as a cancer therapeutic agent. We previously demonstrated that CDDO-Me induces a c-Jun N-terminal kinase (JNK)-mediated DR5 expression and apoptosis. This study revealed the mechanism by which CDDO-Me induces JNK activation and subsequent DR5 upregulation and apoptosis. To determine whether CDDO-Me activates JNK and induces DR5 expression and apoptosis via oxidative stress by inducing the generation of reactive oxygen species (ROS), we examined the effects of various antioxidants on JNK activation, DR5 upregulation, and apoptosis induction by CDDO-Me. Thiol antioxidants, including N-acetyl-L-cycteine (NAC), glutathione (GSH) and dithiothrietol (DTT), abrogated CDDO-Me-induced apoptosis. In contrast, nonthiol antioxidants, including butylated hydroxyanisole (BHA), Trolox, mannitol, and Mn(II) tetra(4-benoic acid) porphyrin chloride ( MnTBAP), failed to do so, with the exception of vitamin C (Vit C). Accordingly, only thiol antioxidants blocked JNK activation induced by CDDO-Me. CDDO-Me reduced intracellular levels of GSH; this reduction was abrogated only by thiol antioxidants and Vit C. However, CDDO-Me did not promote ROS generation. These results suggest that depletion of intracellular GSH, but not ROS generation, contributes to CDDO-Me-induced JNK activation and apoptosis, at least in our systems. Furthermore, these thiol antioxidants abrogated CDDO-Me-induced DR5 expression, whereas the GSH-depleting agent diethylmaleate also upregulated DR5 expression at concentrations that deplete intracellular GSH, demonstrating that GSH depletion can cause DR5 upregulation. Collectively, we conclude that CDDO-Me activates the JNK pathway via depletion of intracellular GSH, leading to DR5 upregulation and induction of apoptosis.