Inhibition of Hec1 expression enhances the sensitivity of human ovarian cancer cells to paclitaxel

Mo, Qingqing; Chen, Pingbo; Jin, Xin; Chen, Qian; Tang, Lan; Wang, Beibei; Li, Kezhen; Wu, Peng; Fang, Yong; Wang, Shixuan; Zhou, Jianfeng; Ma, Ding; Chen, Gang

doi:10.1038/aps.2012.197

Cited by 20 publications

(18 citation statements)

References 23 publications

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“…Expression of the mitotic regulator NDC80 is increased in various human malignancies, including HCC. Considering the significant overexpression of NDC80 in multiple human malignancies[ 23 - 27 ], studies on the mechanisms of NDC80 overexpression are significant. Liu et al[ 28 ] also reported that the expression level of NDC80 was remarkably up-regulated in HBV-related HCC tissues.…”

Section: Discussionmentioning

confidence: 99%

Effect of NDC80 in human hepatocellular carcinoma

Ju¹,

Chen²,

Li³

et al. 2017

WJG

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AIMTo investigate the role of nuclear division cycle (NDC)80 in human hepatocellular carcinogenesis.METHODSNDC80 gene expression was analyzed by real-time reverse transcription polymerase chain reaction in 47 paired hepatocellular carcinoma (HCC) and adjacent tissues. The HCC cell line SMMC-7721 was transfected with lentivirus to silence endogenous NDC80 gene expression, which was confirmed by real-time polymerase chain reaction and western blotting. The effects of NDC80 silencing on SMMC-7721 cell proliferation were evaluated by Cellomics ArrayScan VTI imaging. Cell cycle analysis and apoptosis were detected with flow cytometry. Colony formation was assessed by fluorescence microscopy.RESULTSNDC80 expression levels in HCC tissues were significantly higher than those in the adjacent tissues. Functional studies demonstrated that NDC80 silencing significantly reduced SMMC-7721 cell proliferation and colony formation. Knockdown of NDC80 resulted in increased apoptosis and cell cycle arrest at S-phase. NDC80 contributed to HCC progression by reducing apoptosis and overcoming cell cycle arrest.CONCLUSIONElevated expression of NDC80 may play a role in promoting the development of HCC.

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Section: Discussionmentioning

confidence: 99%

Effect of NDC80 in human hepatocellular carcinoma

Ju¹,

Chen²,

Li³

et al. 2017

WJG

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“…Even though the site of action is very closely associated with microtubules, the potency profile shows that the mechanism of action of TAI-95 has interesting features that may give it an advantage over conventional cytotoxic drugs. A study has showed that Hec1 overexpression was associated with paclitaxel resistance and poor prognosis in ovarian cancer (28), further highlighting the role of the target, Hec1, in drug-resistant cancers. Even though more studies will be necessary to elucidate the underlying mechanisms, the potential of this drug draws immense interest and we hold great expectations on its impact on the clinical treatment of drug-resistant breast cancers.…”

Section: Discussionmentioning

confidence: 99%

Activity of a Novel Hec1-Targeted Anticancer Compound against Breast Cancer Cell Lines In Vitro and In Vivo

Huang¹,

Chang²,

Lee³

et al. 2014

Molecular Cancer Therapeutics

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Current cytotoxic chemotherapy produces clinical benefit in patients with breast cancer but the survival impact is modest. To explore novel cytotoxic agents for the treatment of advanced disease, we have characterized a new and pharmacokinetically improved Hec1-targeted compound, TAI-95. Nine of 11 breast cancer cell lines tested were sensitive to nanomolar levels of TAI-95 (GI 50 ¼ 14.29-73.65 nmol/L), and more importantly, TAI-95 was active on a number of cell lines that were resistant (GI 50 > 10 mmol/L) to other established cytotoxic agents. TAI-95 demonstrates strong inhibition of in vivo tumor growth of breast cancer model when administered orally, without inducing weight loss or other obvious toxicity. Mechanistically, TAI-95 acts by disrupting the interaction between Hec1 and Nek2, leading to apoptotic cell death in breast cancer cells. Furthermore, TAI-95 is active on multidrug-resistant (MDR) cell lines and led to downregulation of the expression of P-glycoprotein (Pgp), an MDR gene. In addition, TAI-95 increased the potency of cytotoxic Pgp substrates, including doxorubicin and topotecan. Certain clinical subtypes of breast cancer more likely to respond to Hec1-targeted therapy were identified and these subtypes are the ones associated with poor prognosis. This study highlights the potential of the novel anticancer compound TAI-95 in difficult-to-treat breast cancers.

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“…47 Before SKOV3-TR30 and A2780-TR cells were collected for quantitative proteomics or western blotting analyses, paclitaxel was removed from complete medium for 7 d.…”

Section: Methodsmentioning

confidence: 99%

TXNDC17 promotes paclitaxel resistance via inducing autophagy in ovarian cancer

Zhang¹,

et al. 2015

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These authors contributed equally to this work.Keywords: autophagy, BECN1, ovarian cancer, paclitaxel resistance, TXNDC17Abbreviations: 95% CI, 95% confidence interval; ALDOC, aldolase C, fructose-bisphosphate; ATG5, autophagy-related 5; BafA1, bafilomycin A 1 ; BECN1, Beclin 1, autophagy-related; CNN3, calponin 3, acidic; DAPI, 4', 6-diamidino-2-phenylindole; FLNA, filamin A, a; GenMAPP, gene microarray pathway profiler; GO, gene ontology; HBSS, Hank's balanced salt solution; HR, hazard ratio; KEGG, Kyoto encyclopedia of genes and genome; LC-MS/MS, liquid chromatography-mass spectrometry/ mass spectrometry; MAP1LC3B/LC3B, microtubule-associated protein 1 light chain 3 b; OS, overall survival; PFS, progression-free survival; PGAM1, phosphoglycerate mutase 1 (brain); siRNA, short interfering RNA; SQSTM1, sequestosome 1; TNF, tumor necrosis factor; TXN, thioredoxin; TXNDC17, thioredoxin domain containing 17; UTP23, small subunit (SSU) processome component, homolog (yeast).Paclitaxel is recommended as a first-line chemotherapeutic agent against ovarian cancer, but drug resistance becomes a major limitation of its success clinically. The key molecule or mechanism associated with paclitaxel resistance in ovarian cancer still remains unclear. Here, we showed that TXNDC17 screened from 356 differentially expressed proteins by LC-MS/MS label-free quantitative proteomics was more highly expressed in paclitaxel-resistant ovarian cancer cells and tissues, and the high expression of TXNDC17 was associated with poorer prognostic factors and exhibited shortened survival in 157 ovarian cancer patients. Moreover, paclitaxel exposure induced upregulation of TXNDC17 and BECN1 expression, increase of autophagosome formation, and autophagic flux that conferred cytoprotection for ovarian cancer cells from paclitaxel. TXNDC17 inhibition by siRNA or enforced overexpression by a pcDNA3.1(C)-TXNDC17 plasmid correspondingly decreased or increased the autophagy response and paclitaxel resistance. Additionally, the downregulation of BECN1 by siRNA attenuated the activation of autophagy and cytoprotection from paclitaxel induced by TXNDC17 overexpression in ovarian cancer cells. Thus, our findings suggest that TXNDC17, through participation of BECN1, induces autophagy and consequently results in paclitaxel resistance in ovarian cancer. TXNDC17 may be a potential predictor or target in ovarian cancer therapeutics.

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Inhibition of Hec1 expression enhances the sensitivity of human ovarian cancer cells to paclitaxel

Cited by 20 publications

References 23 publications

Effect of NDC80 in human hepatocellular carcinoma

Effect of NDC80 in human hepatocellular carcinoma

Activity of a Novel Hec1-Targeted Anticancer Compound against Breast Cancer Cell Lines In Vitro and In Vivo

TXNDC17 promotes paclitaxel resistance via inducing autophagy in ovarian cancer

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