Gli2 silencing enhances TRAIL-induced apoptosis and reduces tumor growth in human hepatoma cells in vivo

Zhang, Dawei; Li, Haiyan; Lau, Wing-Cheong; Cao, Liangqi; Li, Yue; Jiang, Xiaofeng; Yang, Xiao; Xue, Ping

doi:10.4161/15384047.2014.972286

Cited by 11 publications

(8 citation statements)

References 32 publications

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“…Our current results, for the first time, showed that depletion of GLI2 could suppress the proliferation and migration of cervical cancer cells in vitro and their tumorigenicity in vivo. These data were in line with previous observations in other cancer models, where the inhibition of GLI2 was efficient in suppressing tumorigenic properties of prostate cancer cells 17 and hepatoma cells both in vitro and in vivo 18, 19 .…”

Section: Discussionsupporting

confidence: 92%

“…Clearly, our current results were consistent with all of these findings that knockdown GLI2 resulted in cell-cycle arrest at G0/G1, with reduction of cyclin D1 expression and upregulation of p21 and p27 levels, whereas overexpression of GLI2 increased proliferation. Intriguingly, while previous studies reported that GLI2 gene silencing sensitized human hepatoma cells 18, 19 and basal cell carcinoma 23 to tumor necrosis factor-related apoptosis by downregulating c-FLIP and Bcl-2, our result showed that GLI2 knockdown showed no effect on apoptosis using two apoptosis assays, including ELISA assay and Annexin-V FITC Staining. Future studies are needed to determine whether GLI2 are necessary for preventing apoptosis of cervical cancer cells when exposing to apoptosis-inducing agents.…”

Section: Discussioncontrasting

confidence: 55%

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Differential effects of GLI2 and GLI3 in regulating cervical cancer malignancy in vitro and in vivo

Zhu

Xia

Shen

et al. 2018

Laboratory Investigation

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Advanced, recurrent, or persistent cervical cancer is often incurable. Therefore, in-depth insights into the molecular mechanisms are needed for the development of novel therapeutic targets and the improvement of current therapeutic strategies. In this study, we investigated the role of GLI2 and GLI3 in the regulation of the malignant properties of cervical cancer. We showed that down-regulation of GLI2, but not GLI3, with an inducible GLI2 shRNA inhibited the growth and migration of cervical cancer cell lines, which could be rescued by ectopic expression of GLI2. GLI2 appeared to support cell growth by regulating the mitosis, but not the apoptosis, of the cervical cancer cells. Mechanistically, these functions of GLI2 were in part mediated by the activation of AKT pathway. Knockdown of GLI2, but not GLI3, also inhibited xenograft growth of cervical cancer cells in vivo. Finally, analysis of TCGA data showed that high levels of GLI2, but not GLI3, conferred a poor prognosis in cervical cancer patients. These observations for the first time suggest that GLI2, but not GLI3, exerts a tumor-promoting role in cervical cancer and may be targeted as a novel therapeutic strategy.

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Section: Discussionsupporting

confidence: 92%

Section: Discussioncontrasting

confidence: 55%

Differential effects of GLI2 and GLI3 in regulating cervical cancer malignancy in vitro and in vivo

Zhu

Xia

Shen

et al. 2018

Laboratory Investigation

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“…TRAIL could promote apoptosis in various cancer cells but not in normal cells. 3 However, TRAIL resistance occurs in many carcinomas, including endometrial carcinoma. TRAIL resistance is proposed to be due to the action of decoy receptors such as mutation in DR4 (TRAIL-RI) or DR5 (TRAIL-RII), and the dysfunction of DISC components, such as FADD, caspase-8 or 10, and c-FLIP.…”

Section: Introductionmentioning

confidence: 99%

A small compound spindlactone A sensitizes human endometrial cancer cells to TRAIL-induced apoptosis via the inhibition of NAD(P)H dehydrogenase quinone 1

Zhao¹,

Wu²

2018

OTT

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IntroductionSpindlactone A (SPL-A) is a novel small molecule inhibitor of TACC3 that selectively inhibits the nucleation of centrosome microtubules and induces mitotic arrest in ovarian cancer cells. SPL-A is derived from dicoumarol which inhibits the activity of NAD(P)H dehydrogenase quinone oxidoreductase 1 (NQO1). This study aimed to investigate the mechanism by which SPL-A enhances TRAIL-induced apoptosis in endometrial carcinoma cells.Materials and methodsEndometrial carcinoma cells were treated with SPL-A and/or TRAIL, and the apoptosis and protein expression in the treated cells were examined.ResultsCombined treatment with SPL-A and TRAIL significantly induced apoptosis in various human endometrial carcinoma cells, but not in normal human endometrial stromal cells and endometrial epithelial cells. Notably, both NQO1 inhibitor ES936 and NQO1 siRNA enhanced TRAIL-induced apoptosis of endometrial carcinoma cells. Furthermore, SPL-A downregulated the expression of c-FLIP, Bcl-2, Bcl-xl, and Mcl-1, while increasing p53 expression.ConclusionIn particular, luciferase assay showed that SPL-A inhibited Bcl-2 promoter activity, and p53 inhibitor PFT-α could reverse the effect of SPL-A on Bcl-2 expression. Moreover, Bcl-2 overexpression inhibited the apoptosis induced by SPL-A and TRAIL. Taken together, our results suggest that SPL-A sensitizes endometrial cancer cells to TRAIL-induced apoptosis via the regulation of apoptosis-related proteins and the inhibition of NQO1 activity.

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“…In different animal models of hepatocellular carcinoma, the Hh pathway is activated in pre-cancerous tissues and cancerous tumors (Cai et al, 2016). In precursor cancerous cells, Shh promotes proliferation through induction of cyclin B1 and CDK1 mitotic proteins (Cai et al, 2016), while preventing apoptosis (Zhang et al, 2014; Wang et al, 2013). Hh also induces an epithelial to mesenchymal transition in malignant cells, favoring migration and invasiveness (Chen et al, 2014; Byrne et al, 2015).…”

Section: Hedgehog Pathway In Nonalcoholic Fatty Liver Diseasementioning

confidence: 99%

The hedgehog pathway in nonalcoholic fatty liver disease

Machado

Diehl

2018

Critical Reviews in Biochemistry and Molecular Biology

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Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of obesity-associated liver diseases and it has become the major cause of cirrhosis in the Western world. The high prevalence of NAFLD-associated advanced liver disease reflects both the high prevalence of obesity-related fatty liver (hepatic steatosis) and the lack of specific treatments to prevent hepatic steatosis from progressing to more serious forms of liver damage, including nonalcoholic steatohepatitis (NASH), cirrhosis, and primary liver cancer. The pathogenesis of NAFLD is complex, and not fully understood. However, compelling evidence demonstrates that dysregulation of the hedgehog (Hh) pathway is involved in both the pathogenesis of hepatic steatosis and the progression from hepatic steatosis to more serious forms of liver damage. Inhibiting Hedgehog signaling enhances hepatic steatosis, a condition which seldom results in liver-related morbidity or mortality. In contrast, excessive Hedgehog pathway activation promotes development of NASH, cirrhosis, and primary liver cancer, the major causes of liver-related deaths. Thus, suppressing excessive Hh pathway activity is a potential approach to prevent progressive liver damage in NAFLD. Various pharmacologic agents that inhibit Hh signaling are available and approved for cancer therapeutics; more are being developed to optimize the benefits and minimize the risks of inhibiting this pathway. In this review we will describe the Hh pathway, summarize the evidence for its role in NAFLD evolution, and discuss the potential role for Hh pathway inhibitors as therapies to prevent NASH, cirrhosis and liver cancer.

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Gli2 silencing enhances TRAIL-induced apoptosis and reduces tumor growth in human hepatoma cells in vivo

Abstract: y These authors contributed equally to this work.

Cited by 11 publications

References 32 publications

Differential effects of GLI2 and GLI3 in regulating cervical cancer malignancy in vitro and in vivo

Differential effects of GLI2 and GLI3 in regulating cervical cancer malignancy in vitro and in vivo

A small compound spindlactone A sensitizes human endometrial cancer cells to TRAIL-induced apoptosis via the inhibition of NAD(P)H dehydrogenase quinone 1

The hedgehog pathway in nonalcoholic fatty liver disease

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