Glycogen Synthase Kinase-3β: A Prognostic Marker and a Potential Therapeutic Target in Human Bladder Cancer

Naito, Sei; Bilim, Vladimir; Yuuki, Kaori; Ugolkov, Andrey; Motoyama, Teiichi; Nagaoka, Akira; Kato, Tomoyuki; Tomita, Yoshihiko

doi:10.1158/1078-0432.ccr-10-0275

Cited by 77 publications

(88 citation statements)

References 37 publications

(63 reference statements)

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“…We demonstrated that GSK3b expression level increased after treatment with quadruplet combination and concordantly b-catenin, CCND1, and c-Myc mRNA levels decreased. The results were not consistent with the results of Naito et al (2010) for bladder cancer cells except for the decrease in the GSK3b mRNA level after unaccompanied TSA treatment. CCND1 and c-Myc are downstream target genes of b-catenin.…”

Section: Discussioncontrasting

confidence: 96%

“…GSK3b is recognized as much potential tumor suppressor as GSK3 phosphorylated pro-oncogenic molecules such as c-Jun, c-Myc, CREB, CCND1, and b-catenin. Also, GSK3b is known as tumor promoter for certain cancers, such as prostate and renal cancer (Luo et al, 2007;Naito et al, 2010). Naito et al (2010) showed that GSK3b nuclear expression is associated with high-grade tumors, metastasis, and worse survival in bladder cancer patients.…”

Section: Discussionmentioning

confidence: 99%

“…Also, GSK3b is known as tumor promoter for certain cancers, such as prostate and renal cancer (Luo et al, 2007;Naito et al, 2010). Naito et al (2010) showed that GSK3b nuclear expression is associated with high-grade tumors, metastasis, and worse survival in bladder cancer patients. They identified GSK3b as a positive regulator of proliferation and survival of bladder cancer cells (T24, SCaBER, HT1376, and RT4 cell lines).…”

Section: Discussionmentioning

confidence: 99%

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The Epigenetically Regulated Effects of Wnt Antagonists on the Expression of Genes in the Apoptosis Pathway in Human Bladder Cancer Cell Line (T24)

Varol

Konac

Onen

et al. 2014

DNA and Cell Biology

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The epigenetic suppression of Wnt antagonists (sFRPs, DKKs, and WIF-1) causes the activation of both β-catenin and target genes, which play an important role in cell proliferation, metastasis, and angiogenesis. This study is aimed to investigate, on transcriptional and protein levels, the synergic effects of unaccompanied and/or combined use of 5-aza-2'-deoxycytidine (DAC, 5-aza-dC), trichostatin A (TSA), and gemcitabine+cisplatin chemotherapeutic agents on the apoptotic pathway of human bladder cancer cell line T24. The anti-tumor effects of gemcitabine (0-500 nM), cisplatin (0-10 μM), DAC (10 μM), and TSA (300 nM) alone and/or together on T24 cells were determined by WST-1. ELISA method was used to analyze the effects of unaccompanied and combined use of gemcitabine+cisplatin, DAC, and TSA on cell proliferation and determine the cytotoxic and apoptotic dosages at the level of H3 histone acetylation. Methylation-specific PCR was used to evaluate methylation profiles of Wnt antagonist gene (WIF-1). In the case of unaccompanied and/or combined use of specified drugs, the variations in the expression levels of CTNNB1, GSK3β, c-MYC, CCND1, CASP-3, CASP-8, CASP-9, BCL2L1, and WIF-1 genes were determined by quantitative real-time PCR. Our results indicate that through inhibition of DNA methylation, expression of β-catenin and Wnt antagonist re-activation and expressions of canonical Wnt/β-catenin pathway target genes, c-myc and cyclin D1 (CCND1), have decreased. In addition, DAC, TSA, and gemcitabine+cisplatin combination caused an increase in GSK3β mRNA levels, which in turn significantly decreased CCND1 mRNA levels. Moreover, BCL2L1, an anti-apoptotic gene, was downregulated significantly. Meanwhile, both CASP-3 mRNA and active caspase-3 protein levels increased with respect to control (p<0.01). The results revealed that use of quadruplicate gemcitabine+cisplatin+DAC+TSA combination led to a reduced inhibition of canonical Wnt/β-catenin pathway and reduced cell proliferation. Our findings may offer a new approach to consider in the treatment of bladder cancer.

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Section: Discussioncontrasting

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The Epigenetically Regulated Effects of Wnt Antagonists on the Expression of Genes in the Apoptosis Pathway in Human Bladder Cancer Cell Line (T24)

Varol

Konac

Onen

et al. 2014

DNA and Cell Biology

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“…21 It has been reported that SB216763 (ATP-competitive), a GSK3 inhibitor, effectively activated -catenin-mediated transcription. 22 Naito et al 23 showed that GSK3 nuclear expression was associated with highgrade tumors, metastasis, and worse survival in bladder cancer patients. Dose and time-dependent SB216763 improved the cytotoxic effect against the two human urothelial carcinoma cell lines, UMUC3 and UMUC14, suggesting potential therapeutic uses for GSK3 inhibitors.…”

mentioning

confidence: 99%

Does Wnt/β-catenin pathway contribute to the stability of DNMT1 expression in urological cancer cell lines?

Varol

Konac

Bilen

2014

Exp Biol Med (Maywood)

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DNA methylation is considered as one of the most important epigenetic mechanisms and it is catalyzed by DNA methyltransferases (DNMTs). DNMT1 abundance has been frequently seen in urogenital system tumors but the reasons for this abundance are not well understood. We aimed to look into the effects of Wnt/b-catenin signaling pathway on overexpression of DNMT1 and aberrant expression of UHRF1 and HAUSP which are responsible for stability of DNMT1 at transcriptional and protein levels in urogenital cancers. In this context, firstly, Wnt/b-catenin signaling pathway was activated by using SB216763 which is a glycogen synthase kinase-3 (GSK3) b inhibitor. Cell proliferation levels in bladder cancer cells, renal cell carcinoma, and prostate cancer cells treated with GSK3b inhibitor (SB216763) were detected by WST-1 reagent. WIF-1 gene methylation profile was determined by methylation-specific PCR (MSP); expression levels of target genes -catenin and WIF-1 by real-time PCR; and protein levels of -catenin, DNMT1, pGSK3(Ser9), HAUSP, and UHRF1 by Western Blot. Our results indicated that treatment with SB216763 caused an increased cell proliferation at low dose. mRNA levels of -catenin increased after treatment with SB216273 and protein levels of pGSK3b(Ser9), b-catenin, and DNMT1 increased in comparison to control. HAUSP and UHRF1 were either up-regulated or down-regulated at the same doses depending on the type of cancer. Also, we showed that protein levels of DNMT1, b-catenin, HAUSP, and UHRF1 decreased after re-expression of WIF-1 following treatment with DAC. In Caki-2 cells, -catenin pathway might have accounted for the stability of DNMT1 expression, whereas such relation is not valid for T24 and PC3 cells. Our findings may offer a new approach for determination of molecular effects of Wnt/b-catenin signal pathway on DNMT1. This may allow us to identify new molecular targets for the treatment of urogenital cancers.

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“…Especially growth factor receptors usually show stronger reactions after shorter incubation times. Nonspecific GSK3α/β inhibition has already shown antitumor potential in various tumor entities including NETs in vitro [14,21] and in vivo [13,15,22,24]. Although IC 50 values seemed rather high for AR-A014418, in all other in vitro studies performed, similar doses (≥5 µM) of AR-A014418 were necessary in order to obtain significant inhibitory effects on cell survival [34,36,46].…”

Section: Discussionmentioning

confidence: 99%

GSK3α/β: A Novel Therapeutic Target for Neuroendocrine Tumors

Prada¹,

Weis

Orth³

et al. 2017

Neuroendocrinology

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Introduction: Glycogen synthase kinase 3α/β (GSK3α/β) is a serine/threonine kinase that plays a critical role in cancer. Aims: In this study, we evaluated the effects of the specific GSK3α/β inhibitor AR-A014418 in vitro to gain novel insights into GSK3α/β signaling in neuroendocrine tumors (NETs). Materials and Methods: Human NET cell lines (BON1, QGP1, H727, and GOT1) were treated with different concentrations of AR-A014418 alone and in combination with lovastatin, everolimus, 5-fluorouracil (5-FU), and γ-irradiation. Results: AR-A014418 significantly dose- and time-dependently decreased cell viability in all 4 NET cell lines through inhibition of epithelial growth factor receptor and mTORC1/p70S6K signaling, as well as cyclin D3 downregulation and induction of pChk1. In all cell lines tested, FACS analysis showed an AR-A014418-induced increase in the sub-G1 phase, reflecting cell death. Apoptosis induction was observed in H727, GOT1 and QGP1 cells, but not in BON1 cells. Furthermore, significant antimigratory effects upon GSK3α/β inhibition were found and were associated with β-catenin downregulation in all cell lines tested. Compensatory upregulation of pAkt and pERK in response to GSK3α/β inhibition was prevented by combining AR-A014418 with the ERK and Akt inhibitor lovastatin. Accordingly, the lovastatin/AR-A014418 combination was synergistic in BON1 and QGP1 cells. Moreover, AR-A014418 displayed promising chemosensitizing effects on 5-FU in QGP1 and slight radiosensitizing properties in BON1 and QGP1 cells. Conclusion: Our data provide new insights into the role of GSK3α/β in NETs and suggest that GSK3α/β inhibition could be a novel therapeutic option in NETs, especially in combination with lovastatin or 5-FU, depending on tumor entity.

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Glycogen Synthase Kinase-3β: A Prognostic Marker and a Potential Therapeutic Target in Human Bladder Cancer

Cited by 77 publications

References 37 publications

The Epigenetically Regulated Effects of Wnt Antagonists on the Expression of Genes in the Apoptosis Pathway in Human Bladder Cancer Cell Line (T24)

The Epigenetically Regulated Effects of Wnt Antagonists on the Expression of Genes in the Apoptosis Pathway in Human Bladder Cancer Cell Line (T24)

Does Wnt/β-catenin pathway contribute to the stability of DNMT1 expression in urological cancer cell lines?

GSK3α/β: A Novel Therapeutic Target for Neuroendocrine Tumors

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