Glycogen synthase kinase-3: a new therapeutic target in renal cell carcinoma

Bilim, Vladimir; Ougolkov, Andrei V.; Yuuki, Kaori; Naito, Sei; Kawazoe, Hisashi; Muto, Andrea; Oya, Mototsugu; Billadeau, Daniel D.; Motoyama, Teiichi; Tomita, Yoshihiko

doi:10.1038/sj.bjc.6605437

Cited by 94 publications

(117 citation statements)

References 34 publications

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“…GSK-3β has been reported as a candidate target in leukemia and other malignancies (13)(14)(15)(16)(17)(18). In this manuscript, we report a role for GSK-3α in human AML.…”

Section: Introductionmentioning

confidence: 72%

The intersection of genetic and chemical genomic screens identifies GSK-3α as a target in human acute myeloid leukemia

Banerji¹,

Frumm²,

Ross³

et al. 2012

J. Clin. Invest.

103

112

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Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Long-term survival of patients with AML has changed little over the past decade, necessitating the identification and validation of new AML targets. Integration of genomic approaches with small-molecule and genetically based high-throughput screening holds the promise of improved discovery of candidate targets for cancer therapy. Here, we identified a role for glycogen synthase kinase 3α (GSK-3α) in AML by performing 2 independent small-molecule library screens and an shRNA screen for perturbations that induced a differentiation expression signature in AML cells. GSK-3 is a serine-threonine kinase involved in diverse cellular processes, including differentiation, signal transduction, cell cycle regulation, and proliferation. We demonstrated that specific loss of GSK-3α induced differentiation in AML by multiple measurements, including induction of gene expression signatures, morphological changes, and cell surface markers consistent with myeloid maturation. GSK-3α-specific suppression also led to impaired growth and proliferation in vitro, induction of apoptosis, loss of colony formation in methylcellulose, and anti-AML activity in vivo. Although the role of GSK-3β has been well studied in cancer development, these studies support a role for GSK-3α in AML.

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“…GSK-3β has been reported as a candidate target in leukemia and other malignancies (13)(14)(15)(16)(17)(18). In this manuscript, we report a role for GSK-3α in human AML.…”

Section: Introductionmentioning

confidence: 72%

The intersection of genetic and chemical genomic screens identifies GSK-3α as a target in human acute myeloid leukemia

Banerji¹,

Frumm²,

Ross³

et al. 2012

J. Clin. Invest.

103

112

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“…Untreated 0.5 mM 1 mM 10 mM 20 mM (days) % % % % % ------------------------------------------------- -------------------------------------------------data, lithium effects can be assigned to GSK-3ß inhibition (32,33), rather than to a specific Wnt activation, even if this molecular pathway is altered by the drug in both cell lines. On the other hand, the clinical dose of 1 mM lithium elicits anti-neoplastic effects only in D283MED cells.…”

Section: -------------------------------------------------Timementioning

confidence: 99%

Lithium induces mortality in medulloblastoma cell lines

et al. 2010

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Abstract. Lithium is the main therapeutic agent for the treatment of bipolar disorders but nerve cells are not the sole target of this drug. Indeed, lithium has been reported to target numerous cell types and to affect cell proliferation, differentiation and death. Lithium targets a variety of enzymes among which there is GSK-3ß and a number of cell responses elicited by lithium are mediated by the Wnt pathway that is involved in medulloblastoma (MB) pathogenesis. We studied the in vitro effects of lithium on two different MB cell lines: D283MED and DAOY. High doses of lithium inhibited GSK3-ß, decreased cell proliferation and induced nonapoptotic cell death in both cell lines independently by intracellular levels of ß-catenin that is consistently high only in D283MED. At clinical doses, the anti-neoplastic effects were observed only in this cell line, highlighting the importance of a specific molecular background in determining the target therapy response. In conclusion, lithium could be a promising drug in MB, but an accurate molecular profile predictive of drug response still needs to be clarified.

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“…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. 24 Bilim et al 25 showed that GSK3 inhibitors could decrease viability of renal cancer cell lines. Therefore, nuclear accumulation of GSK3 is a new promising marker of human renal cell carcinoma (RCC) cells.…”

mentioning

confidence: 99%

“…Therefore, nuclear accumulation of GSK3 is a new promising marker of human renal cell carcinoma (RCC) cells. 25 GSK3 is up-regulated in prostate cancer. 26 SB216763 was able to increase -catenin expression level in androgen receptor (AR) positive and negative cell lines.…”

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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Glycogen synthase kinase-3: a new therapeutic target in renal cell carcinoma

Cited by 94 publications

References 34 publications

The intersection of genetic and chemical genomic screens identifies GSK-3α as a target in human acute myeloid leukemia

The intersection of genetic and chemical genomic screens identifies GSK-3α as a target in human acute myeloid leukemia

Lithium induces mortality in medulloblastoma cell lines

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

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