Peroxiredoxin IV plays a critical role in cancer cell growth and radioresistance through the activation of the Akt/GSK3 signaling pathways.
Peroxiredoxin IV plays a critical role in cancer cell growth and radioresistance through the activation of the Akt/GSK3 signaling pathways.
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过氧化还蛋白IV通过激活Akt/GSK3信号通路在癌细胞生长和辐射抵抗中发挥关键作用。
DOI：
10.1016/j.jbc.2022.102123
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发表时间：
2022-07
影响因子：
4.8
通讯作者：
Wei, Qiou
中科院分区：
文献类型：
--
作者：
Ding, Na;Jiang, Hong;Thapa, Pratik;Hao, Yanning;Alshahrani, Aziza;Allison, Derek;Izumi, Tadahide;Rangnekar, Vivek M.;Liu, Xiaoqi;Wei, Qiou
在各种类型的人类癌症中通常观察到高水平的氧化还原酶，尽管这些酶是否以及如何导致癌症恶性程度和治疗抗性尚未被理解。Peroxiredoxin IV（Prx 4）是一种具有真正过氧化物酶和分子伴侣功能的抗氧化剂。在这里，我们报告说，Prx 4在前列腺癌患者标本中高度表达，以及建立前列腺癌细胞系，其水平可以通过激活雄激素受体信号传导进一步刺激。我们使用慢病毒介导的shRNA敲低和基于CRISPR-Cas9的KO技术来建立Prx 4耗尽的前列腺癌细胞，与对照细胞相比，其显示出延迟的细胞周期进展，降低的细胞增殖、迁移和侵袭速率。此外，我们使用蛋白质组分析仪磷酸激酶阵列来识别Prx 4缺失细胞中的信号变化;我们发现Prx 4的缺失导致Akt及其下游激酶GSK 3 α/β的磷酸化不足。此外，我们证明Prx 4-耗尽的细胞对电离辐射更敏感，因为它们显示出破坏活性氧的能力和增加DNA损伤的积累。在小鼠异种移植模型中，我们显示Prx 4的耗尽导致肿瘤生长的显著抑制，并且由Prx 4耗尽的细胞形成的肿瘤对放射治疗的反应更有效。我们的研究结果表明，Prx 4水平的增加有助于通过激活Akt/GSK 3信号通路的前列腺癌的恶性和放射抗性。因此，靶向Prx 4的策略可用于潜在地抑制肿瘤生长并克服前列腺癌中的放射抗性。
High levels of redox enzymes have been commonly observed in various types of human cancer, although whether and how the enzymes contribute to cancer malignancy and therapeutic resistance have yet to be understood. Peroxiredoxin IV (Prx4) is an antioxidant with bona fide peroxidase and molecular chaperone functions. Here, we report that Prx4 is highly expressed in prostate cancer patient specimens, as well as established prostate cancer cell lines, and that its levels can be further stimulated through the activation of androgen receptor signaling. We used lentivirus-mediated shRNA knockdown and CRISPR-Cas9 based KO techniques to establish Prx4-depleted prostate cancer cells, which showed delayed cell cycle progression, reduced rate of cell proliferation, migration, and invasion compared to control cells. In addition, we used proteome profiler phosphokinase arrays to identify signaling changes in Prx4-depleted cells; we found that loss of Prx4 results in insufficient phosphorylation of both Akt and its downstream kinase GSK3α/β. Moreover, we demonstrate that Prx4-depleted cells are more sensitive to ionizing radiation as they display compromised ability to scavenge reactive oxygen species and increased accumulation of DNA damage. In mouse xenograft models, we show depletion of Prx4 leads to significant suppression of tumor growth, and tumors formed by Prx4-depleted cells respond more effectively to radiation therapy. Our findings suggest that increased levels of Prx4 contribute to the malignancy and radioresistance of prostate cancer through the activation of Akt/GSK3 signaling pathways. Therefore, strategies targeting Prx4 may be utilized to potentially inhibit tumor growth and overcome radioresistance in prostate cancer.
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DOI：
10.1074/jbc.m111.298810
发表时间：
2011-12-09
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Cao Z;Tavender TJ;Roszak AW;Cogdell RJ;Bulleid NJ
通讯作者：
Bulleid NJ
影响因子：
14.8
作者：
Liang, Chun-Chi;Park, Ann Y.;Guan, Jun-Lin
通讯作者：
Guan, Jun-Lin
DOI：
10.1073/pnas.1902651116
发表时间：
2019-06-04
影响因子：
11.1
作者：
Abida, Wassim;Cyrta, Joanna;Sawyers, Charles L.
通讯作者：
Sawyers, Charles L.
将前列腺癌细胞 AR 异质性与不同的去势和恩杂鲁胺反应联系起来。
影响因子：
16.6
作者：
Li Q;Deng Q;Chao HP;Liu X;Lu Y;Lin K;Liu B;Tang GW;Zhang D;Tracz A;Jeter C;Rycaj K;Calhoun-Davis T;Huang J;Rubin MA;Beltran H;Shen J;Chatta G;Puzanov I;Mohler JL;Wang J;Zhao R;Kirk J;Chen X;Tang DG
通讯作者：
Tang DG
影响因子：
11.4
作者：
Alessi, DR;Andjelkovic, M;Hemmings, BA
通讯作者：
Hemmings, BA