Ursodeoxycholic Acid Inhibits Glioblastoma Progression via Endoplasmic Reticulum Stress Related Apoptosis and Synergizes with the Proteasome Inhibitor Bortezomib.,ACS Chemical Neuroscience

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Ursodeoxycholic Acid Inhibits Glioblastoma Progression via Endoplasmic Reticulum Stress Related Apoptosis and Synergizes with the Proteasome Inhibitor Bortezomib.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-04-10 , DOI: 10.1021/acschemneuro.0c00095
Zhong Yao _{1,

2,

3} , Xun Zhang _{2,

3} , Feihu Zhao _{2,

3} , Shuai Wang _{2,

3} , Anjing Chen _{2,

3} , Bin Huang _{2,

3} , Jian Wang _{2,

3,

4} , Xingang Li _{1,

2}

Affiliation

Ursodeoxycholic acid (UDCA) has demonstrated cancer suppressive potential in several tumors. Here, we investigated the antitumor potential and biochemical mechanism of UDCA on glioblastoma multiforme (GBM), the deadliest form of brain cancer with a median survival of 15 months. Cell viability was assessed using the CCK-8 and colony forming assays. Expression profiles were obtained using RNA sequencing, and PCR and Western blot were used to validate changes in related markers at the RNA and protein levels. Flow cytometry was used to examine cell cycle, apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS). UDCA inhibited GBM cell viability in a dose- and time-dependent manner. Flow cytometry demonstrated that cells were arrested in the G1 phase and underwent apoptosis. The RNA sequencing results showed UDCA treatment in part targeted gene expression related to mitochondria and endoplasmic reticulum (ER). UDCA indeed led to decreased MMP, overproduction of ROS, and ER stress. Three critical ER stress sensors ATF6, IRE1α, and PERK were increased in the acute phase. Additionally, combining UDCA with the proteasome inhibitor bortezomib (BTZ) achieved a synergistic effect through enhancing the PERK/ATF4/CHOP pathway and protracting ER stress. UDCA inhibited GBM progression, and the combination with BTZ achieved a synergistic effect via protracted ER stress. Thus, UDCA, alone or with combination of BTZ, shows promise as a possible therapeutic agent for the treatment of GBM.

中文翻译：

熊去氧胆酸通过内质网应激相关的凋亡抑制胶质母细胞瘤进展，并与蛋白酶体抑制剂硼替佐米协同作用。

熊去氧胆酸（UDCA）已在多种肿瘤中显示出抑制癌症的潜力。在这里，我们研究了UDCA对胶质母细胞瘤（GBM）的抗肿瘤潜力和生化机制，胶质母细胞瘤是最致命的脑癌，中位生存期为15个月。使用CCK-8和集落形成测定法评估细胞活力。使用RNA测序获得表达谱，并使用PCR和Western blot验证RNA和蛋白质水平上相关标记的变化。流式细胞仪用于检查细胞周期，凋亡，线粒体膜电位（MMP）和活性氧（ROS）。UDCA以剂量和时间依赖性方式抑制GBM细胞的活力。流式细胞仪显示细胞被阻滞在G1期并发生凋亡。RNA测序结果显示，UDCA处理了与线粒体和内质网（ER）相关的部分靶向基因表达。UDCA确实导致MMP降低，ROS过度产生和ER应激。在急性期增加了三个关键的ER应力传感器ATF6，IRE1α和PERK。此外，将UDCA与蛋白酶体抑制剂硼替佐米（BTZ）结合使用可通过增强PERK / ATF4 / CHOP途径和延长ER应激来达到协同作用。UDCA抑制GBM进程，并且与BTZ的结合通过延长的ER应力达到了协同作用。因此，UDCA单独或与BTZ结合使用，有望成为治疗GBM的可能治疗剂。和ER压力。在急性期增加了三个关键的ER应力传感器ATF6，IRE1α和PERK。此外，将UDCA与蛋白酶体抑制剂硼替佐米（BTZ）结合使用可通过增强PERK / ATF4 / CHOP途径和延长ER应激来达到协同作用。UDCA抑制GBM进程，并且与BTZ的结合通过延长的ER应力达到了协同作用。因此，UDCA单独或与BTZ结合使用，有望成为治疗GBM的可能治疗剂。和ER压力。在急性期增加了三个关键的ER应力传感器ATF6，IRE1α和PERK。此外，将UDCA与蛋白酶体抑制剂硼替佐米（BTZ）结合使用可通过增强PERK / ATF4 / CHOP途径和延长ER应激来达到协同作用。UDCA抑制GBM进程，并且与BTZ的结合通过延长的ER应力达到了协同作用。因此，UDCA单独或与BTZ结合使用，有望成为治疗GBM的可能治疗剂。并且与BTZ的结合通过延长的ER应力达到了协同作用。因此，UDCA单独或与BTZ结合使用，有望成为治疗GBM的可能治疗剂。并且与BTZ的结合通过延长的ER应力达到了协同作用。因此，UDCA单独或与BTZ结合使用，有望成为治疗GBM的可能治疗剂。

更新日期：2020-04-02

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