Involvement of thioredoxin-binding protein 2 in the antitumor activity of CD437
Involvement of thioredoxin-binding protein 2 in the antitumor activity of CD437
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DOI：
10.1111/j.1349-7006.2008.00979.x
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发表时间：
2008-12-01
期刊：
影响因子：
5.7
通讯作者：
Shiota, Goshi
中科院分区：
文献类型：
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作者：
Matsuoka, Saori;Tsuchiya, Hiroyuki;Shiota, Goshi
本作者之前报道，尽管对天然类维生素A没有反应，但合成类维生素A CD437可诱导卵巢腺癌细胞内质网应激介导的细胞凋亡。然而，其促凋亡作用的确切机制尚未完全确定。本文中的本研究证明CD437诱导卵巢腺癌SKOV3细胞凋亡涉及通过依赖于细胞内钙浓度的机制上调硫氧还蛋白结合蛋白2(TBP2)。 TBP2 已知可结合并抑制硫氧还蛋白 (TRX) 活性，而 TRX 通过抑制凋亡信号调节激酶 1 (ASK1) 具有抗凋亡作用。 CD437 诱导 TBP2 后，观察到 ASK1 及其下游分子 c-Jun N 末端激酶的激活。有趣的是，CD437 诱导 TBP2 与 TRX 结合，进而促进 ASK1 从 TRX 解离。此外，小干扰RNA (siRNA) 阻断TBP2 诱导可显着减弱CD437 的细胞毒性作用。这些结果表明TBP2在CD437对SKOV3细胞发挥促凋亡作用的机制中发挥着关键作用。 （癌症科学 2008 年；99：2485-2490）。
The present authors previously reported that a synthetic retinoid, CD437, induces endoplasmic reticulum stress-mediated apoptosis in ovarian adenocarcinoma cells in spite of no response to natural retinoids. However, the precise mechanism of its proapoptotic action has not been fully determined. The present study herein demonstrates that apoptosis induction of ovarian adenocarcinoma SKOV3 cells by CD437 involves the upregulation of thioredoxin-binding protein 2 (TBP2) by a mechanism that is dependent on the intracellular calcium concentration. TBP2 is known to bind to and suppress thioredoxin (TRX) activity whereas TRX has an anti-apoptotic effect by inhibiting apoptosis signal-regulating kinase 1 (ASK1). The activation of ASK1 and its downstream molecule, c-Jun N-terminal kinase, was observed after induction of TBP2 by CD437. Interestingly, CD437 induced the association of TBP2 with TRX and, in turn, facilitated the dissociation of ASK1 from TRX. Moreover, blockade of TBP2 induction by small interfering RNA (siRNA) significantly attenuated the cytotoxic effect of CD437. These results suggest that TBP2 plays a critical role in the mechanism by which CD437 exerts proapoptotic action against SKOV3 cells. (Cancer Sci 2008; 99: 2485-2490).