TXNDC9 regulates oxidative stress-induced androgen receptor signaling to promote prostate cancer progression
TXNDC9 regulates oxidative stress-induced androgen receptor signaling to promote prostate cancer progression
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TXNDC9 调节氧化应激诱导的雄激素受体信号传导以促进前列腺癌进展
DOI：
10.1038/s41388-019-0991-3
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发表时间：
2020-01-01
期刊：
影响因子：
8
通讯作者：
Han, Bo
中科院分区：
文献类型：
--
作者：
Feng, Tingting;Zhao, Ru;Han, Bo
活性氧（ROS）和ROS诱导的氧化应激与前列腺癌（PCa）的发展和去势抵抗性肿瘤的进展有关。这部分是通过雄激素受体（AR）信号的激活。然而，ROS激活AR的分子基础仍然知之甚少。在这里，我们报道了含硫氧还蛋白结构域9 （TXNDC9）是ROS触发AR信号的重要调节因子。TXNDC9的表达被ROS诱导剂上调，TXNDC9在患者肿瘤中的表达升高与临床分期的进展有关。TXNDC9促进PCa细胞存活和增殖。它是氧化应激条件下AR蛋白表达和AR转录活性所必需的。从机制上讲，ROS诱导剂促进TXNDC9与PRDX1分离，但增强了与MDM2的蛋白结合。同时，PRDX1增强了其与AR的关联。这些蛋白质相互作用交换不仅导致MDM2蛋白降解，还导致PRDX1介导的AR蛋白稳定，并随后升高AR信号。通过其抑制剂Conoidin A （CoA）阻断PRDX1，即使在雄激素缺乏的条件下，也能抑制AR信号、PCa细胞增殖和异种移植物肿瘤的生长。当与恩杂鲁胺联合治疗时，辅酶a的肿瘤抑制作用进一步增强。综上所述，这些研究表明TXNDC9-PRDX1轴在ROS激活AR功能中起着重要作用。它提供了一个原理证明，共同靶向AR和PRDX1可能更有效地控制PCa的生长。
Reactive oxygen species (ROS) and ROS-induced oxidative stress are associated with prostate cancer (PCa) development and castrate-resistant tumor progression. This is in part through the activation of the androgen receptor (AR) signaling. However, the molecular underpinning of ROS to activate AR remains poorly understood. Here, we report that the thioredoxin domain-containing 9 (TXNDC9) is an important regulator of ROS to trigger AR signaling. TXNDC9 expression is upregulated by ROS inducer, and increased TXNDC9 expression in patient tumors is associated with advanced clinical stages. TXNDC9 promotes PCa cell survival and proliferation. It is required for AR protein expression and AR transcriptional activity under oxidative stress conditions. Mechanistically, ROS inducers promote TXNDC9 to dissociate from PRDX1, but enhance a protein association with MDM2. Concurrently, PRDX1 enhances its association with AR. These protein interaction exchanges result in not only MDM2 protein degradation, but also PRDX1 mediated AR protein stabilization, and subsequent elevation of AR signaling. Blocking PRDX1 by its inhibitor, Conoidin A (CoA), suppresses AR signaling, PCa cell proliferation, and xenograft tumor growth even under androgen-deprived conditions. These tumor-suppressive effects of CoA were further strengthened when in combination with enzalutamide treatment. Together, these studies demonstrate that the TXNDC9-PRDX1 axis plays an important role for ROS to activate AR functions. It provides a proof-of-principle that co-targeting AR and PRDX1 may be more effective to control PCa growth.