Antitumor agent PX-12 inhibits HIF-1α protein levels through an Nrf2/PMF-1-mediated increase in spermidine/spermine acetyl transferase.
Antitumor agent PX-12 inhibits HIF-1α protein levels through an Nrf2/PMF-1-mediated increase in spermidine/spermine acetyl transferase.
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DOI：
10.1007/s00280-010-1500-0
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发表时间：
2011-08
影响因子：
3
通讯作者：
Powis, Garth
中科院分区：
文献类型：
--
作者：
Kim, Yon Hui;Coon, Amy;Baker, Amanda F.;Powis, Garth
硫氧还蛋白 -1（Trx -1）的氧化还原信号调节细胞生长和存活的多个方面，并且肿瘤中Trx -1水平升高与患者生存率降低相关。PX -12是一种目前处于临床开发阶段的Trx -1抑制剂，已被发现可降低缺氧诱导因子 -1α（HIF -1α）转录因子在肿瘤中的水平。据报道，多胺调节因子1（SSAT1）可与HIF -1α和受体活化蛋白激酶C受体1（RACK1）结合，导致不依赖氧的HIF -1泛素化和降解。多胺调节因子2（SSAT2），一种相关蛋白，可稳定希佩尔 - 林道（VHL）蛋白和延伸蛋白C与HIF -1的相互作用，导致依赖氧的HIF -1α泛素化和降解。我们研究了PX -12和Trx -1对SSAT1、SSAT2以及对HIF -1α抑制的影响。
用PX -12处理一组细胞系，以研究其对SSAT1和SSAT2表达以及对HIF -1α蛋白水平的影响。我们还评估了通过核因子E2相关因子2（Nrf2）和多胺调节因子1伴侣蛋白（PMF -1）这两种反式作用转录因子对SSAT1的调节。
我们发现PX -12增加了核Nrf2活性以及抗氧化反应元件结合。PX -12还以一种不依赖Trx -1且依赖PMF -1的方式增加了SSAT1的表达，但不增加SSAT2的表达。抑制Nrf2或PMF -1可阻止PX -12引起的SSAT1增加。
结果表明，PX -12独立于Trx -1发挥作用，增加核Nrf2，核Nrf2与PMF -1相互作用增加SSAT1的表达。HIF -1α与SSAT1结合导致的降解可能解释了PX -12引起的HIF -1α降低，并且可能有助于PX -12的抗肿瘤活性。
Thioredoxin-1 (Trx-1) redox signaling regulates multiple aspects of cell growth and survival, and elevated tumor levels of Trx-1 have been associated with decreased patient survival. PX-12, an inhibitor of Trx-1 currently in clinical development, has been found to decrease tumor levels of the HIF-1α transcription factor. SSAT1 has been reported to bind to HIF-1α and RACK1, resulting in oxygen-independent HIF-1 ubiquitination and degradation. SSAT2, a related protein, stabilizes the interaction of the VHL protein and elongin C with HIF-1 leading to oxygen-dependent HIF-1α ubiquitination and degradation. We investigated the effects of PX-12 and Trx-1 on SSAT1, SSAT2, and inhibition of HIF-1α. A panel of cell lines was treated with PX-12 to investigate its effects on SSAT1 and SSAT2 expression, and on HIF-1α protein levels. We also evaluated the regulation of SSAT1 through the Nrf2 and PMF-1, two trans-acting transcription factors. We found that PX-12 increased nuclear Nrf2 activity and antioxidant response element binding. PX-12 also increased the expression of SSAT1 but not SSAT2 in a PMF-1-dependent manner that was independent of Trx-1. Inhibition of Nrf2 or PMF-1 prevented the increase in SSAT1 caused by PX-12. The results show that PX-12, acting independently of Trx-1, increases nuclear Nrf2, which interacts with PMF-1 to increase the expression of SSAT1. The degradation of HIF-1α that results from binding with SSAT1 may explain the decrease in HIF-1α caused by PX-12 and could contribute to the antitumor activity of PX-12.
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影响因子：
4.1
作者：
Chen, Y;Vujcic, S;Porter, CW
通讯作者：
Porter, CW
影响因子：
4.8
作者：
Baek, Jin Hyen;Liu, Ye V.;Semenza, Gregg L.
通讯作者：
Semenza, Gregg L.
影响因子：
9.3
作者：
Lau, Alexandria;Villeneuve, Nicole F.;Sun, Zheng;Wong, Pak Kin;Zhang, Donna D.
通讯作者：
Zhang, Donna D.
影响因子：
4.8
作者：
Baek, Jin H.;Liu, Ye V.;Semenza, Gregg L.
通讯作者：
Semenza, Gregg L.
影响因子：
4.1
作者：
Wang, YL;Devereux, W;Casero, RA
通讯作者：
Casero, RA