TTK inhibition increases cisplatin sensitivity in high-grade serous ovarian carcinoma through the mTOR/autophagy pathway

Abstract

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.

Chromatin Separation Regulators Predict the Prognosis and Immune Microenvironment Estimation in Lung Adenocarcinoma

“…KIF14 is confirmed to promote cancer cell proliferation and contribute to chemoresistance (Singel et al, 2014;Xiao et al, 2021). Silencing TTK is also found to inhibit the proliferation and invasion and increase radiosensitivity and chemosensitivity of cancer cells (Chen S. et al, 2019;Huang et al, 2020;Zhang et al, 2021b;Qi et al, 2021). ESPL1 is determined to be a novel prognostic biomarker and is associated with the malignant features in several cancers (Finetti et al, 2014;Wang R. et al, 2020;Liu Z. et al, 2021).…”

Inhibition of apoptosis through AKT-mTOR pathway in ovarian cancer and renal cancer

“…TTK functions in relation to cell proliferation and enhances Aurora kinase B activity [16]. TTK is a regulator of cell cycle, [17], and is linked to tumorigenesis [18]. TTK can help bladder cancer cells activity and mediate epithelial-mesenchymal transition [19].…”

Single-cell and bulk RNA sequencing reveal ligands and receptors associated with worse overall survival in serous ovarian cancer

“…Drugs targeting the PI3K-AKT signaling pathway, such as BEZ235, AZD5363, and NSC777213, have been tested to treat ovarian cancer with promising results [85][86][87]. A phase I trial with PI3-kinase inhibitor BKM120 in combination with PARP inhibitor olaparib is being conducted in patients with high-grade serous ovarian cancer, with evidence of clinical benefits [88]. The pharmacological and genetic inhibition of TTK, which is involved in the PI3K-AKT pathway, decreases the proliferation of ovarian cancer cells and increases their sensitivity to cisplatin by suppressing autophagy [89].…”