KRIBB11 Induces Apoptosis in A172 Glioblastoma Cells via MULE-Dependent Degradation of MCL-1.
KRIBB11 Induces Apoptosis in A172 Glioblastoma Cells via MULE-Dependent Degradation of MCL-1.
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DOI：
10.3390/molecules26144165
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发表时间：
2021-07-08
期刊：
影响因子：
--
通讯作者：
Lee JH
中科院分区：
文献类型：
--
作者：
Yoo K;Yun HH;Jung SY;Lee JH
KRIBB 11是一种HSF 1抑制剂，已被证明可使各种类型的癌细胞对几种抗癌药物的治疗敏感。然而，KRIBB 11在阻止胶质母细胞瘤细胞生长中的独特作用及其相关机制尚未阐明。在此，我们的目的是检查KRIBB 11作为胶质母细胞瘤的抗癌剂的潜力。通过MTT法、克隆形成实验和Western blotting检测c-PARP，我们证明KRIBB 11通过诱导细胞凋亡抑制A172胶质瘤细胞的生长。在分子水平上，KRIBB 11降低了抗凋亡蛋白MCL-1水平，这归因于MULE泛素连接酶水平的增加。然而，A172细胞中HSF 1的组成性活性不受KRIBB 11的排他性处理的影响。此外，基于放线菌酮追踪试验，我们发现KRIBB 11显著地延缓了MULE的降解。总之，KRIBB 11处理后MULE的稳定显然是A172细胞中MCL-1降解和随后诱导凋亡的重要步骤。我们的研究结果扩展了KRIBB 11控制的分子通路的知识，并可能有效地开发胶质母细胞瘤的抑制性治疗策略。
KRIBB11, an HSF1 inhibitor, was shown to sensitize various types of cancer cells to treatment with several anticancer drugs. However, the exclusive effects of KRIBB11 in preventing the growth of glioblastoma cells and the related mechanisms have not been elucidated yet. Herein, we aimed to examine the potential of KRIBB11 as an anticancer agent for glioblastoma. Using MTT and colony formation assays and Western blotting for c-PARP, we demonstrated that KRIBB11 substantially inhibits the growth of A172 glioma cells by inducing apoptosis. At the molecular level, KRIBB11 decreased anti-apoptotic protein MCL-1 levels, which was attributable to the increase in MULE ubiquitin ligase levels. However, the constitutive activity of HSF1 in A172 cells was not influenced by the exclusive treatment with KRIBB11. Additionally, based on cycloheximide chase assay, we found that KRIBB11 markedly retarded the degradation of MULE. In conclusion, stabilization of MULE upon KRIBB11 treatment is apparently an essential step for degradation of MCL-1 and the subsequent induction of apoptosis in A172 cells. Our results have expanded the knowledge on molecular pathways controlled by KRIBB11 and could be potentially effective for developing an inhibitory therapeutic strategy for glioblastoma.
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影响因子：
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作者：
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影响因子：
158.5
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10.1073/pnas.1200731109
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