Dual inhibition of HSF1 and DYRK2 impedes cancer progression.
Dual inhibition of HSF1 and DYRK2 impedes cancer progression.
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DOI：
10.1042/bsr20222102
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发表时间：
2023-01-31
影响因子：
4
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中科院分区：
文献类型：
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保持蛋白质稳态是癌症的主要生存机制。双特异性酪氨酸磷酸化调节激酶 2 (DYRK2) 是一种关键的致癌激酶，可直接激活转录因子热休克因子 1 (HSF1) 和 26S 蛋白酶体。事实证明，针对 DYRK2 是一种针对对蛋白毒性应激敏感的癌症的易于处理的策略；然而，HSF1抑制剂的开发仍处于起步阶段。重要的是，多种其他激酶已被证明可以过度激活 HSF1，这促进了直接靶向 HSF1 的想法。 HSF1 直接抑制剂 KRIBB11 的最终开发表明该转录因子确实是一个可药物靶标。目前的研究表明，HSF1 和 DYRK2 的同时靶向确实可以通过比单独靶向更快地诱导细胞凋亡来阻止癌症。此外，靶向 DYRK2-HSF1 轴可诱导蛋白酶体抑制剂耐药细胞死亡，并减少异位和原位异种移植模型中的三阴性乳腺癌 (TNBC) 负担。这些数据共同表明，激酶 DYRK2 及其底物 HSF1 的共靶向可能被证明是干扰肿瘤恶性肿瘤的有益策略。
Preserving proteostasis is a major survival mechanism for cancer. Dual specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) is a key oncogenic kinase that directly activates the transcription factor heat-shock factor 1 (HSF1) and the 26S proteasome. Targeting DYRK2 has proven to be a tractable strategy to target cancers sensitive to proteotoxic stress; however, the development of HSF1 inhibitors remains in its infancy. Importantly, multiple other kinases have been shown to redundantly activate HSF1 that promoted ideas to directly target HSF1. The eventual development of direct HSF1 inhibitor KRIBB11 suggests that the transcription factor is indeed a druggable target. The current study establishes that concurrent targeting of HSF1 and DYRK2 can indeed impede cancer by inducing apoptosis faster than individual targetting. Furthermore, targeting the DYRK2-HSF1 axis induces death in proteasome inhibitor-resistant cells and reduces triple-negative breast cancer (TNBC) burden in ectopic and orthotopic xenograft models. Together the data indicate that cotargeting of kinase DYRK2 and its substrate HSF1 could prove to be a beneficial strategy in perturbing neoplastic malignancies.
DOI：
10.3390/molecules26144165
发表时间：
2021-07-08
期刊：
Molecules (Basel, Switzerland)
影响因子：
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作者：
Yoo K;Yun HH;Jung SY;Lee JH
通讯作者：
Lee JH