TTK inhibition increases cisplatin sensitivity in high-grade serous ovarian carcinoma through the mTOR/autophagy pathway.
TTK inhibition increases cisplatin sensitivity in high-grade serous ovarian carcinoma through the mTOR/autophagy pathway.
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TTK 抑制通过 mTOR/自噬途径增加高级别浆液性卵巢癌的顺铂敏感性
DOI：
10.1038/s41419-021-04429-6
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发表时间：
2021-12-07
影响因子：
9
通讯作者：
Kong B
中科院分区：
文献类型：
--
作者：
Qi G;Ma H;Li Y;Peng J;Chen J;Kong B
高级别浆液性卵巢癌（HGSOC）是最致命的妇科恶性肿瘤。然而，HGSOC发生、进展、化疗不敏感和耐药的分子机制尚不清楚。我们分析了两个独立的GEO数据集，包括原发性卵巢癌和正常对照的基因表达谱，以确定与HGSOC发生和进展相关的基因。差异表达基因（DEGs）的KEGG通路分析显示，细胞周期通路是最富集的通路，其中TTK蛋白激酶（TTK）是唯一具有临床级抑制剂的基因，已在临床试验中研究，但未在HGSOC中研究。从另外两个数据集来看，TTK在顺铂耐药卵巢癌细胞中也上调。TTK是纺锤体组装检查点信号的调节因子，在多种癌症的细胞周期控制和肿瘤发生中发挥重要作用。然而TTK在HGSOC中的作用和调控机制尚不明确。在这项研究中，我们观察到TTK在HGSOC患者中上调。TTK高表达与预后不良有关。遗传和药理抑制TTK通过干扰细胞周期进程和增加细胞凋亡来抑制卵巢癌细胞的增殖。TTK沉默通过激活哺乳动物雷帕霉素靶蛋白（mTOR）复合物，进一步抑制体外顺铂诱导的自噬，从而增加顺铂敏感性。此外，在TTK敲低细胞中，雷帕霉素介导的mTOR抑制部分降低了增强的敏感性。此外，TTK敲低通过减少自噬增加顺铂在体内的毒性。这些发现表明TTK抑制剂联合顺铂可能会提高TTK高表达的HGSOC患者对顺铂的反应率。综上所述，本研究可为今后采用顺铂联合TTK抑制剂治疗HGSOC提供理论基础。
High-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy. However, the molecular mechanisms underlying HGSOC development, progression, chemotherapy insensitivity and resistance remain unclear. Two independent GEO datasets, including the gene expression profile of primary ovarian carcinoma and normal controls, were analyzed to identify genes related to HGSOC development and progression. A KEGG pathway analysis of the differentially expressed genes (DEGs) revealed that the cell cycle pathway was the most enriched pathway, among which TTK protein kinase (TTK) was the only gene with a clinical-grade inhibitor that has been investigated in a clinical trial but had not been studied in HGSOC. TTK was also upregulated in cisplatin-resistant ovarian cancer cells from two other datasets. TTK is a regulator of spindle assembly checkpoint signaling, playing an important role in cell cycle control and tumorigenesis in various cancers. However, the function and regulatory mechanism of TTK in HGSOC remain to be determined. In this study, we observed TTK upregulation in patients with HGSOC. High TTK expression was related to a poor prognosis. Genetic and pharmacological inhibition of TTK impeded the proliferation of ovarian cancer cells by disturbing cell cycle progression and increasing apoptosis. TTK silencing increased cisplatin sensitivity by activating the mammalian target of rapamycin (mTOR) complex to further suppress cisplatin-induced autophagy in vitro. In addition, the enhanced sensitivity was partially diminished by rapamycin-mediated inhibition of mTOR in TTK knockdown cells. Furthermore, TTK knockdown increased the toxicity of cisplatin in vivo by decreasing autophagy. These findings suggest that the administration of TTK inhibitors in combination with cisplatin may lead to improved response rates to cisplatin in patients with HGSOC presenting high TTK expression. In summary, our study may provide a theoretical foundation for using the combination therapy of cisplatin and TTK inhibitors as a treatment for HGSOC in the future.
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影响因子：
3.7
作者：
Chen, Saipeng;Wang, Jianan;Yang, Kuo
通讯作者：
Yang, Kuo
Mps1 激酶动态定位至动粒对于纺锤体微管的精确附着至关重要
DOI：
10.1073/pnas.1508791112
发表时间：
2015-08-18
影响因子：
11.1
作者：
Dou, Zhen;Liu, Xing;Yao, Xuebiao
通讯作者：
Yao, Xuebiao
影响因子：
11.2
作者：
Colombo, Riccardo;Caldarelli, Marina;Moll, Juergen
通讯作者：
Moll, Juergen
ARHGEF17是将MPS1靶向动力学的必不可少的主轴组件检查点因子。
DOI：
10.1083/jcb.201408089
发表时间：
2016-03-14
期刊：
The Journal of cell biology
影响因子：
--
作者：
Isokane M;Walter T;Mahen R;Nijmeijer B;Hériché JK;Miura K;Maffini S;Ivanov MP;Kitajima TS;Peters JM;Ellenberg J
通讯作者：
Ellenberg J
影响因子：
7.3
作者：
Kusakabe, Ken-ichi;Ide, Nobuyuki;Nakamura, Yusuke
通讯作者：
Nakamura, Yusuke