PMID- 34876569 OWN - NLM STAT- MEDLINE DCOM- 20220408 LR - 20230210 IS - 2041-4889 (Electronic) VI - 12 IP - 12 DP - 2021 Dec 7 TI - TTK inhibition increases cisplatin sensitivity in high-grade serous ovarian carcinoma through the mTOR/autophagy pathway. PG - 1135 LID - 10.1038/s41419-021-04429-6 [doi] LID - 1135 AB - 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. CI - (c) 2021. The Author(s). FAU - Qi, Gonghua AU - Qi G AD - Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 250012, Jinan, China. AD - Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital, Shandong University, 250012, Jinan, China. FAU - Ma, Hanlin AU - Ma H AD - Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 250012, Jinan, China. AD - Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital, Shandong University, 250012, Jinan, China. FAU - Li, Yingwei AU - Li Y AD - Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 250012, Jinan, China. AD - Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital, Shandong University, 250012, Jinan, China. FAU - Peng, Jiali AU - Peng J AD - Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 250012, Jinan, China. AD - Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital, Shandong University, 250012, Jinan, China. FAU - Chen, Jingying AU - Chen J AD - Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 250012, Jinan, China. AD - Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital, Shandong University, 250012, Jinan, China. FAU - Kong, Beihua AU - Kong B AUID- ORCID: 0000-0002-5911-0242 AD - Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, 250012, Jinan, China. kongbeihua@sdu.edu.cn. AD - Gynecologic Oncology Key Laboratory of Shandong Province, Qilu Hospital, Shandong University, 250012, Jinan, China. kongbeihua@sdu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20211207 PL - England TA - Cell Death Dis JT - Cell death & disease JID - 101524092 RN - 0 (Cell Cycle Proteins) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.10.1 (Protein-Tyrosine Kinases) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) RN - EC 2.7.12.1 (TTK protein, human) RN - Q20Q21Q62J (Cisplatin) SB - IM MH - Autophagy/genetics MH - Cell Cycle Proteins MH - Cell Line, Tumor MH - *Cisplatin/pharmacology/therapeutic use MH - Extracellular Signal-Regulated MAP Kinases MH - Humans MH - *Ovarian Neoplasms/drug therapy/genetics/pathology MH - Protein Serine-Threonine Kinases MH - Protein-Tyrosine Kinases MH - TOR Serine-Threonine Kinases/genetics PMC - PMC8651821 COIS- The authors declare no competing interests. EDAT- 2021/12/09 06:00 MHDA- 2022/04/09 06:00 PMCR- 2021/12/07 CRDT- 2021/12/08 05:56 PHST- 2021/06/03 00:00 [received] PHST- 2021/11/22 00:00 [accepted] PHST- 2021/11/09 00:00 [revised] PHST- 2021/12/08 05:56 [entrez] PHST- 2021/12/09 06:00 [pubmed] PHST- 2022/04/09 06:00 [medline] PHST- 2021/12/07 00:00 [pmc-release] AID - 10.1038/s41419-021-04429-6 [pii] AID - 4429 [pii] AID - 10.1038/s41419-021-04429-6 [doi] PST - epublish SO - Cell Death Dis. 2021 Dec 7;12(12):1135. doi: 10.1038/s41419-021-04429-6.