XAV939, a tankyrase 1 inhibitior, promotes cell apoptosis in neuroblastoma cell lines by inhibiting Wnt/β-catenin signaling pathway

Tian, Xiaohong; Hou, Wei; Fang, Yan; Fan, Jun; Tu, Hao; Bai, Shuling; Qu, Chen; Xu, He; Li, Yan

doi:10.1186/1756-9966-32-100

Cited by 104 publications

(72 citation statements)

References 34 publications

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“…Previous studies showed that treatment of human mesenchymal stromal cells with XAV939 significantly decreased ALP activity [24]. Moreover, XAV939 induced cell apoptosis in neuroblastoma cells [25]. Here, we treated HAVICs with XAV939 and found that the latter dose-dependently decreased the number of HAVICs.…”

Section: Discussionmentioning

confidence: 64%

Assessing Calcification Onset in Aortic Valve Interstitial Cells

Khan¹,

B²,

Al‐Kindi³

et al. 2017

Cardiovasc Pharm Open Access

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IntroductionAortic valve stenosis (AVS) is a complex disease, characterized by the thickening of the aortic valve with significant fibrosis and/or calcification [1]. Short-term symptoms include shortness of breath and fainting, while more long-term symptoms include heart failure and inevitably, death [2]. Treatment for AVS remains non-existent, with surgical intervention being the only viable option for at-risk patients. Thus, there has been interest in finding innovative approaches to treating this perilous disease [3,4].The pathogenesis of AVS is an active process involving multiple cell types and complexed underlying mechanisms [5,6]. Upon differentiation of mesenchymal-like cells to chondrogenic cells, matrix vesicles are released, containing enzymes and other factors that lead to the onset of calcification [7]. One of these enzymes, alkaline phosphatase (ALP), is a metalloenzyme that has been shown to play a profound role in calcification onset by concentrating calcium [8], mineralizing hydroxyapatite crystals [8], and inactivating inhibitory polyphosphates [9]. In humans, there are four ALP isozymes: alkaline phosphatase, tissue-nonspecific isozyme (TNALP), intestinal-type alkaline phosphatase, placental-type alkaline phosphatase, and placental-like alkaline phosphatase [10]. Two isoforms of TNALP exist: bone-specific TNALP and liver-specific TNALP, both of which are abundantly found in the serum [10]. Within the context of vascular calcification, bone TNALP is highly expressed in calcifying vascular smooth muscle cells and is likely to be responsible for calcium deposition and AVS pathogenesis [10].A multitude of studies draw conclusions regarding the pathogenesis of AVS in humans by utilizing aortic valve interstitial cells from bovine [11][12][13]. The ultimate goal of these studies is to identify mechanisms that will help us better understand calcification onset in humans. However, there is a need to directly compare these animal models to humans and assess whether or not it is plausible to make such a AbstractAortic valve stenosis (AVS) is one of the most common heart valve diseases, and surgical intervention remains the only viable treatment option. Thus, there is a need for novel and innovative treatments. One approach is to study the biological pathogenesis of this disease in hopes of finding new targets for drug therapy. Although this may be a viable option, it faces some methodological concerns. Many studies attempted to address the underlying mechanisms of this disease using aortic valves from bovine models. Although these may be viable models in certain diseased conditions, this may not be the case when studying calcification in AVS. Thus, the aim of our study was to assess the significance of drawing conclusions from bovine models to humans in the context of AVS, and investigate the role of alkaline phosphatase (ALP), an enzyme that increases calcium mineralization and deposition in aortic valve calcification. We also wanted to identify any differences in calcification when using different os...

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Section: Discussionmentioning

confidence: 64%

Assessing Calcification Onset in Aortic Valve Interstitial Cells

Khan¹,

B²,

Al‐Kindi³

et al. 2017

Cardiovasc Pharm Open Access

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“…Therefore, the therapeutic effect is not satisfactory. Previous studies found that XAV939, a TNKS1 inhibitor, inhibited the proliferation of colon cancer and neuroblastoma (NB) cells, presumably by preventing PARsylation of TRF1 (8) or by inhibiting the Wnt/β-catenin signaling pathway (14,15) and causing a downstream DNA damage response (15,16). At present, it is not clear whether XAV939 affects telomere length and telomerase activity in NB cells.…”

Section: Introductionmentioning

confidence: 78%

“…Studies have shown that targeted inhibition of GSK-3β protein greatly affected cell proliferation and telomere length, suggesting a relationship between telomere maintenance and Wnt signaling pathways (31). Our previous study also demonstrated that XAV939 induced the apoptosis of NB cells as detected by Annexin V and Hoechst 33342 staining as well as decreased expression of Bcl-2 (14). In agreement with previous research, the cell apoptosis was confirmed by TEM and FCM, and decreased invasive ability was detected by invasion assay following XAV939 treatment or RNAi-TNKS1.…”

Section: Discussionmentioning

confidence: 94%

“…SH-SY5Y cells were cultured and proliferated for XAV939 and RNAi treatment. XAV939 was dissolved in dimethyl sulfoxide (DMSO; Sigma-Aldrich), and the final concentration was 1 µM based on our previous study results (14). The control group was treated with DMSO only.…”

Section: Methodsmentioning

confidence: 99%

“…The percentage of apoptotic cells was calculated as the ratio of apoptotic to total cells. The mean and standard error were calculated for each time point and treatment group (14).…”

Section: Quantitative Real-time Polymerase Chain Reaction (Qpcr)mentioning

confidence: 99%

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XAV939 promotes apoptosis in a neuroblastoma cell line via telomere shortening

et al. 2014

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Abstract. Telomeres, telomerase and tankyrase (TNKS) have an extremely important and special association with human cell aging and cancer. Telomerase activity is abnormally high in cancer cells and is accompanied by the overexpression of tankyrase 1 (TNKS1). TNKS1 is a positive regulator of telomerase activation and telomere extension in the human body, indicating that TNKS1 may be a possible therapeutic target for cancer. XAV939 is a small-molecule inhibitor of TNKS1. The objective of the present study was to investigate the apoptotic effect of XAV939 on the neuroblastoma (NB) SH-SY5Y cell line, as well as the change in telomere length and telomerase activity and elucidate the mechanism from this perspective. In the present study, we initially treated SH-SY5Y cells with XAV939 and RNA interference (RNAi)-TNKS1, and subsequently chose the optimal sequence for RNAi-TNKS1. We then measured the telomere length using quantitative real-time polymerase chain reaction (qPCR) assay, detected the telomerase activity using the ELISA kit, observed apoptotic morphology by transmission electron microscopy, and detected the percentages of apoptotic cells using flow cytometry and Hoechst 33342 staining. We also determined the invasive ability by a cell invasion assay. The results showed that short hairpin RNA-2 (shRNA-2) was the optimal sequence for RNAi-TNKS1. Treatment with both XAV939 and RNAi-TNKS1 shortened the telomere length, promoted apoptosis and reduced the invasive ability of the SH-SY5Y cells, yet had no effect on telomerase activity. XAV939 promoted apoptosis and reduced the invasiveness of SH-SY5Y cells dependent on telomere shortening, and further research should be conducted to clarify the exact mechanisms. This research may contribute to the cure of malignant NB using multi-targeted therapy with small-molecule agents. IntroductionTelomeres, telomerase and tankyrase (TNKS) have an extremely important and special association with human 'cell aging' and 'immortalized cells', offering new opportunities for the research of senescence and cancer. Telomere is a short DNA-protein complex that presents in the linear chromosome ends of eukaryotic cells and constitutes a special hat-like structure along with telomere-binding proteins to maintain the integrity of chromosomes. Telomerase is a ribonucleoprotein complex of RNA and protein composition, and belongs to the reverse transcriptases. Subunits of the human telomerase gene include telomerase RNA (hTR), telomerase binding protein (hTP1) and telomerase activity catalytic unit (hTERT). The main function of telomerase is to maintain telomere length. Telomeres can use the 3' end as primers, their own RNA as a template to synthesize telomere repeat sequences of TTAGGG, and add these to chromosome ends to maintain the original length of the telomere. Telomerase activity has been found in germ and stem cells, which have self-renewal capacity, and in 80-95% of tumors, yet it is weak or has no activity in normal somatic cells (1). Telomerase activity gradually disappears with ...

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Dissecting the differentiation process of the preplacodal ectoderm in zebrafish

Yao

Zhao

et al. 2014

Developmental Dynamics

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Background: The preplacodal region (PPR) is a region of specialized ectoderm at the border of neural and nonneural ectoderm (NNE). Coordinated Bmp, Fgf, and Wnt signals are known to drive PPR development; however, the underlying mechanism is unknown. Results: We identified key components involved in PPR differentiation. The mesoderm/marginal Wnts at the early gastrula stage trigger differentiation by allowing the adjacent NNE border cells to start adopting caudal PPR fates; otherwise, the development of caudal PPR identity is hindered due to the persistent presence of gata3 mRNA. The caudal PPR fate dominates when foxi1 expression is enhanced at the late gastrula stage, and depleting Foxi1 after 6 hours postfertilization (hpf) reduces the otic-epibranchial placodal domain. When the Gata3 level is manipulated at the fertilized egg stage or near 6 hpf, the lens is always affected. In establishing PPR polarity, both Gata3 and Foxi1 inhibit Bmp signaling, whereas Foxi1 inhibits, but Gata3 enhances, Fgf sensitivity of the PPR cells. Conclusions: Our study reveals that in zebrafish, (1) the PPR at the shield stage may enter a developmental state when the PPR cells preferentially adopt a particular placodal fate and (2) a network of genetically linked factors, including Wnt/beta-catenin, Fgfr, Bmp, Gata3, and Foxi1, direct the process of PPR differentiation.

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XAV939, a tankyrase 1 inhibitior, promotes cell apoptosis in neuroblastoma cell lines by inhibiting Wnt/β-catenin signaling pathway

Cited by 104 publications

References 34 publications

Assessing Calcification Onset in Aortic Valve Interstitial Cells

Assessing Calcification Onset in Aortic Valve Interstitial Cells

XAV939 promotes apoptosis in a neuroblastoma cell line via telomere shortening

Dissecting the differentiation process of the preplacodal ectoderm in zebrafish

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