TTK regulates proliferation and apoptosis of gastric cancer cells through the Akt‐mTOR pathway

Huang, Huilian; Yang, Yadong; Zhang, Wenyuan; Liu, Xinzhu; Yang, Geng

doi:10.1002/2211-5463.12909

Cited by 33 publications

(23 citation statements)

References 23 publications

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“…To investigate whether RAE1 could be a therapeutic target, we performed a comprehensive analysis of 276 genes encoding microtubule‐regulating proteins 19 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 using TCGA data and evaluated their potential efficacy as a therapeutic target. We calculated the fold change in mRNA expression of each gene in tumor tissues compared to normal tissues, the correlation between mRNA expression and DNA copy number, and whether the high expression group was associated with poor prognosis.…”

Section: Resultsmentioning

confidence: 99%

Mitotic checkpoint regulator RAE1 promotes tumor growth in colorectal cancer

et al. 2021

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Microtubules are among the most successful targets for anticancer therapy because they play important roles in cell proliferation as they constitute the mitotic spindle, which is critical for chromosome segregation during mitosis. Hence, identifying new therapeutic targets encoding proteins that regulate microtubule assembly and function specifically in cancer cells is critical. In the present study, we identified a candidate gene that promotes tumor progression, ribonucleic acid export 1 (RAE1), a mitotic checkpoint regulator, on chromosome 20q through a bioinformatics approach using datasets of colorectal cancer (CRC), including The Cancer Genome Atlas (TCGA). RAE1 was ubiquitously amplified and overexpressed in tumor cells. High expression of RAE1 in tumor tissues was positively associated with distant metastasis and was an independent poor prognostic factor in CRC. In vitro and in vivo analysis showed that RAE1 promoted tumor growth, inhibited apoptosis, and promoted cell cycle progression, possibly with a decreased proportion of multipolar spindle cells in CRC. Furthermore, RAE1 induced chemoresistance through its anti–apoptotic effect. In addition, overexpression of RAE1 and significant effects on survival were observed in various types of cancer, including CRC. In conclusion, we identified RAE1 as a novel gene that facilitates tumor growth in part by inhibiting apoptosis and promoting cell cycle progression through stabilizing spindle bipolarity and facilitating tumor growth. We suggest that it is a potential therapeutic target to overcome therapeutic resistance of CRC.

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Section: Resultsmentioning

confidence: 99%

Mitotic checkpoint regulator RAE1 promotes tumor growth in colorectal cancer

et al. 2021

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“…TTK plays an important role in cell division, and its expression is higher in many human malignancies. Silencing of TTK in PCa, gastric and pancreatic cancer cells inhibited cell proliferation, invasion and migration, and increased apoptosis (Kaistha et al, 2014;Chen et al, 2019;Huang et al, 2020). Thus, it suggests that the inhibition of TTK by MS13 treatment may inhibit cell proliferation and induce apoptosis in AIPC cells.…”

Section: Discussionmentioning

confidence: 95%

Diarylpentanoid (1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadiene-3-one) (MS13) Exhibits Anti-proliferative, Apoptosis Induction and Anti-migration Properties on Androgen-independent Human Prostate Cancer by Targeting Cell Cycle–Apoptosis and PI3K Signalling Pathways

et al. 2021

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Diarylpentanoids exhibit a high degree of anti-cancer activity and stability in vitro over curcumin in prostate cancer cells. Hence, this study aims to investigate the effects of a diarylpentanoid, 1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadiene-3-one (MS13) on cytotoxicity, anti-proliferative, apoptosis-inducing, anti-migration properties, and the underlying molecular mechanisms on treated androgen-independent prostate cancer cells, DU 145 and PC-3. A cell viability assay has shown greater cytotoxicity effects of MS13-treated DU 145 cells (EC50 7.57 ± 0.2 µM) and PC-3 cells (EC50 7.80 ± 0.7 µM) compared to curcumin (EC50: DU 145; 34.25 ± 2.7 µM and PC-3; 27.77 ± 6.4 µM). In addition, MS13 exhibited significant anti-proliferative activity against AIPC cells compared to curcumin in a dose- and time-dependent manner. Morphological observation, increased caspase-3 activity, and reduced Bcl-2 protein levels in these cells indicated that MS13 induces apoptosis in a time- and dose-dependent. Moreover, MS13 effectively inhibited the migration of DU 145 and PC-3 cells. Our results suggest that cell cycle-apoptosis and PI3K pathways were the topmost significant pathways impacted by MS13 activity. Our findings suggest that MS13 may demonstrate the anti-cancer activity by modulating DEGs associated with the cell cycle-apoptosis and PI3K pathways, thus inhibiting cell proliferation and cell migration as well as inducing apoptosis in AIPC cells.

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“…TTK inhibits the PI3K/AKT pathway, and TTK knockdown inhibits the PKCα/ERK signaling pathway in colon cancer [ 20 ]. Huang et al [ 19 ] and Liu et al [ 14 ] found that TTK activates the Akt/mTOR pathway in gastric and liver cancer. All the aforementioned signaling pathways are involved in regulating autophagy; thus, we focused on the regulatory relationship between TTK and autophagy in ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

Cell Death Dis

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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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TTK regulates proliferation and apoptosis of gastric cancer cells through the Akt‐mTOR pathway

Cited by 33 publications

References 23 publications

Mitotic checkpoint regulator RAE1 promotes tumor growth in colorectal cancer

Mitotic checkpoint regulator RAE1 promotes tumor growth in colorectal cancer

Diarylpentanoid (1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadiene-3-one) (MS13) Exhibits Anti-proliferative, Apoptosis Induction and Anti-migration Properties on Androgen-independent Human Prostate Cancer by Targeting Cell Cycle–Apoptosis and PI3K Signalling Pathways

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

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