Heat Shock Protein 90 Triggers Multi-Drug Resistance of Ovarian Cancer via AKT/GSK3β/β-Catenin Signaling.
Heat Shock Protein 90 Triggers Multi-Drug Resistance of Ovarian Cancer via AKT/GSK3β/β-Catenin Signaling.
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热休克蛋白 90 通过 AKT/GSK3 beta/beta-Catenin 信号触发卵巢癌的多药耐药性
DOI：
10.3389/fonc.2021.620907
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发表时间：
2021
影响因子：
4.7
通讯作者：
Zhao Y
中科院分区：
文献类型：
--
作者：
Yin L;Yang Y;Zhu W;Xian Y;Han Z;Huang H;Peng L;Zhang K;Zhao Y
卵巢癌是最致命的妇科肿瘤，多药耐药是其治疗的主要障碍。热休克蛋白90(Hsp90)参与了肿瘤的恶性行为。然而，其在卵巢癌多药耐药中的作用和机制尚不清楚。我们的结果表明，Hsp90在多药耐药的卵巢癌细胞中过表达。用shHsp90或抑制剂BIIB021下调HSP90基因表达，可增加卵巢癌细胞对紫杉醇和顺铂的敏感性，增强药物诱导的细胞凋亡。HSP90正向调控与多药耐药密切相关的多药耐药蛋白1(P-gp/MDR1)、乳腺癌耐药蛋白(BCRP)、Survivin和Bcl2的表达。此外，HSP90的过表达促进了β-连环蛋白的积累，而HSP90的下调则降低了β-连环蛋白的积累、核转位和转录活性。我们还发现β-连环蛋白参与了热休克蛋白90介导的P-gp、bcrp、Survivin和Bcl2的表达。此外，HSP90增强了AKT/GSK3β信号转导，AKT信号在HSP90诱导的β-连环蛋白的积聚和转录活性以及紫杉醇和顺铂的多药耐药中起关键作用。综上所述，HSP90增强了AKT/GSK3β/β-连环蛋白信号转导通路，诱导卵巢癌多药耐药。通过抑制AKT/GSK3AKT/GSK3β/β-Catenin信号转导途径抑制Hsp90化疗敏感的卵巢癌细胞多药耐药，为卵巢癌的成功治疗提供了一种有前景的治疗策略。
Ovarian cancer is the most lethal gynaecologic tumor, with which multi-drug resistance as the major therapeutic hindrance. Heat shock protein 90 (Hsp90) has been involved in cancer malignant behaviors. However, its role and mechanism in multi-drug resistance of ovarian cancer remains poorly understood. Our results demonstrated that Hsp90 was overexpressed in multi-drug resistant ovarian cancer cells. Hsp90 downregulation by shHsp90 or inhibitor BIIB021 increased the sensitivity of multi-drug resistant ovarian cancer cells to paclitaxel and cisplatin, and augmented the drugs-induced apoptosis. Hsp90 positively regulated the expressions of multi-drug resistance protein 1 (P-gp/MDR1), breast cancer resistance protein (BCRP), Survivin and Bcl-2 expressions closely associated with multi-drug resistance. Moreover, overexpression of Hsp90 promoted β-catenin accumulation, while Hsp90 downregulation decreased the accumulation, nuclear translocation and transcriptional activity of β-catenin. We also identified that β-catenin was responsible for Hsp90-mediated expressions of P-gp, BCRP, Survivin, and Bcl-2. Furthermore, Hsp90 enhanced the AKT/GSK3β signaling, and AKT signaling played a critical role in Hsp90-induced accumulation and transcriptional activity of β-catenin, as well as multi-drug resistance to paclitaxel and cisplatin. In conclusion, Hsp90 enhanced the AKT/GSK3β/β-catenin signaling to induce multi-drug resistance of ovarian cancer. Suppressing Hsp90 chemosensitized multi-drug resistant ovarian cancer cells via impairing the AKT/GSK3β/β-catenin signaling, providing a promising therapeutic strategy for a successful treatment of ovarian cancer.
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影响因子：
15
作者：
He C;Poon C;Chan C;Yamada SD;Lin W
通讯作者：
Lin W
影响因子：
11.2
作者：
Condelli, Valentina;Piscazzi, Annamaria;Landriscina, Matteo
通讯作者：
Landriscina, Matteo
影响因子：
11.4
作者：
Campone, M;Vavasseur, F;Oliver, L
通讯作者：
Oliver, L
影响因子：
5.6
作者：
Dinic, Jelena;Podolski-Renic, Ana;Pesic, Milica
通讯作者：
Pesic, Milica
DOI：
10.1176/appi.ajp.2009.08121873
发表时间：
2010-04
期刊：
The American journal of psychiatry
影响因子：
--
作者：
Freyberg Z;Ferrando SJ;Javitch JA
通讯作者：
Javitch JA