当前位置: X-MOL 学术Mol. Cancer Ther. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Aurora B kinase promotes CHIP-dependent degradation of HIF1a in prostate cancer cells
Molecular Cancer Therapeutics ( IF 5.3 ) Pub Date : 2019-12-17 , DOI: 10.1158/1535-7163.mct-19-0777
Kuntal Biswas 1 , Sukumar Sarkar 1 , Neveen Said 1 , David L Brautigan 2 , James M Larner 1
Affiliation  

Hypoxia is a major factor in tumor progression and resistance to therapies, which involves elevated levels of the transcription factor HIF1α. Here, we report that prostate tumor xenografts express high levels of HIF1α and show greatly enhanced growth in response to knockdown of the E3 ligase CHIP (C-terminus of Hsp70-interacting protein). In multiple human prostate cancer cell lines under hypoxia, taxol treatment induces the degradation of HIF1α, and this response is abrogated by knockdown of CHIP, but not by E3 ligase VHL or RACK1. HIF1α degradation is accompanied by loss of function, evidenced by reduced expression of HIF1α-dependent genes. CHIP-dependent HIF1α degradation also occurs in cells arrested in mitosis by nocodazole instead of taxol. Mitotic kinase Aurora B activity is required for taxol-induced HIF1α degradation. Purified Aurora B directly phosphorylates HIF1α at multiple sites, and these modifications enhance its polyubiquitination by CHIP in a purified reconstituted system. Our results show how activation of Aurora B promotes CHIP-dependent degradation of HIF1α in prostate cancer cells. This new knowledge may affect the use of mitotic kinase inhibitors and open new approaches for treatment of hypoxic prostate tumors.

中文翻译:

Aurora B激酶促进前列腺癌细胞中HIF1a的CHIP依赖性降解

缺氧是肿瘤进展和治疗抵抗的主要因素,其中涉及转录因子 HIF1α 水平升高。在这里,我们报告前列腺肿瘤异种移植物表达高水平的 HIF1α 并显示出响应于 E3 连接酶 CHIP(Hsp70 相互作用蛋白的 C 端)的敲低而大大增强的生长。在缺氧条件下的多个人前列腺癌细胞系中,紫杉醇处理诱导 HIF1α 降解,这种反应会被 CHIP 的敲低消除,但不会被 E3 连接酶 VHL 或 RACK1 消除。HIF1α 降解伴随着功能丧失,HIF1α 依赖性基因的表达减少就证明了这一点。CHIP 依赖​​性 HIF1α 降解也发生在由诺考达唑而不是紫杉醇阻止有丝分裂的细胞中。紫杉醇诱导的 HIF1α 降解需要有丝分裂激酶 Aurora B 活性。纯化的 Aurora B 在多个位点直接磷酸化 HIF1α,这些修饰增强了其在纯化重组系统中通过 CHIP 的多泛素化。我们的结果显示了 Aurora B 的激活如何促进前列腺癌细胞中 HIF1α 的 CHIP 依赖​​性降解。这一新知识可能会影响有丝分裂激酶抑制剂的使用,并开辟治疗缺氧前列腺肿瘤的新方法。
更新日期:2019-12-17
down
wechat
bug