Inactivation of glycogen synthase kinase-3β, a downstream target of the raf-1 pathway, is associated with growth suppression in medullary thyroid cancer cells

Kunnimalaiyaan, Muthusamy; Vaccaro, Abram; Ndiaye, Mary A.; Chen, Herbert

doi:10.1158/1535-7163.mct-06-0665

Cited by 98 publications

(121 citation statements)

References 37 publications

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“…Here, we show that inhibition of GSK-3 suppresses proliferation and survival of renal cancer cells. Our data are in agreement with other studies showing that inhibition of GSK-3 results in decreased proliferation and/or survival of CLL (Ougolkov et al, 2007), pancreatic , colorectal (Shakoori et al, 2005), ovarian (Cao et al, 2006), thyroid (Kunnimalaiyaan et al, 2007) and brain (Kotliarova et al, 2008) cancer cells. We also observed retardation of tumour growth by GSK-3 pharmacological inhibition in mice xenograft model using RCC cell lines (manuscript in preparation).…”

Section: Discussionsupporting

confidence: 93%

“…Recent studies show that GSK-3b has an important function in pathogenesis of human cancer, including leukaemia (Ougolkov et al, 2007;Wang et al, 2008), pancreatic (Ougolkov et al, , 2006, prostate (Mazor et al, 2004;Sun et al, 2007), colorectal (Shakoori et al, 2005), ovarian (Cao et al, 2006), thyroid (Kunnimalaiyaan et al, 2007) and brain (Kotliarova et al, 2008) carcinomas. However, the role of GSK-3b in kidney cancer remains unknown.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2009

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BACKGROUND: Renal cell carcinoma (RCC) is highly resistant to chemotherapy because of a high apoptotic threshold. Recent evidences suggest that GSK-3b positively regulates human pancreatic cancer and leukaemia cell survival in part through regulation of nuclear factor (NF-kB)-mediated expression of anti-apoptotic molecules. Our objectives were to determine the expression pattern of GSK-3b and to assess the anti-cancer effect of GSK-3b inhibition in RCC. METHODS: Immunohistochemistry and nuclear/cytosolic fractionation were performed to determine the expression pattern of GSK-3b in human RCCs. We used small molecule inhibitor, RNA interference, western blotting, quantitative RT -PCR, BrDU incorporation and MTS assays to study the effect of GSK-3b inactivation on renal cancer cell proliferation and survival. RESULTS: We detected aberrant nuclear accumulation of GSK-3b in RCC cell lines and in 68 out of 74 (91.89%) human RCCs. We found that pharmacological inhibition of GSK-3 led to a decrease in proliferation and survival of renal cancer cells. We observed that inhibition of GSK-3 results in decreased expression of NF-kB target genes Bcl-2 and XIAP and a subsequent increase in renal cancer cell apoptosis. Moreover, we show that GSK-3 inhibitor and Docetaxel synergistically suppress proliferation and survival of renal cancer cells. CONCLUSIONS: Our results show nuclear accumulation of GSK-3b as a new marker of human RCC, identify that GSK-3 positively regulates RCC cell survival and proliferation and suggest inhibition of GSK-3 as a new promising approach in the treatment of human renal cancer.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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

et al. 2009

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“…So far GSK3B has been described to be involved in modulating biological processes as opposite as proliferation or apoptosis, depending on the cellular, molecular, and developmental context (28)(29)(30)(31)(32)(33)(34)(35)(36)(37). In fact, GSK3B is known to play an antiproliferative role by promoting APC-dependent phosphorylation-and hence proteosome-mediated degradation-of b-catenin, a transcription factor positively regulating Myc and cyclin D1 expression (14).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of GSK3B Bypass Drug Resistance of p53-Null Colon Carcinomas by Enabling Necroptosis in Response to Chemotherapy

Grassilli

Narloch

Federzoni

et al. 2013

Clinical Cancer Research

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Purpose: Evasion from chemotherapy-induced apoptosis due to p53 loss strongly contributes to drug resistance. Identification of specific targets for the treatment of drug-resistant p53-null tumors would therefore increase the effectiveness of cancer therapy.Experimental Design: By using a kinase-directed short hairpin RNA library and HCT116p53KO drugresistant colon carcinoma cells, glycogen synthase kinase 3 beta (GSK3B) was identified as a target whose silencing bypasses drug resistance due to loss of p53. p53-null colon cancer cell lines with different sets of mutations were used to validate the role of GSK3B in sustaining resistance and to characterize cell death mechanisms triggered by chemotherapy when GSK3B is silenced. In vivo xenograft studies were conducted to confirm resensitization of drug-resistant cells to chemotherapy upon GSK3 inhibition. Colon cancer samples from a cohort of 50 chemotherapy-treated stage II patients were analyzed for active GSK3B expression.Results: Downregulation of GSK3B in various drug-resistant p53-null colon cancer cell lines abolished cell viability and colony growth after drug addition without affecting cell proliferation or cell cycle in untreated cells. Cell death of 5-fluorouracil (5FU)-treated p53-null GSK3B-silenced colon carcinoma cells occurred via PARP1-dependent and AIF-mediated but RIP1-independent necroptosis. In vivo studies showed that drug-resistant xenograft tumor mass was significantly reduced only when 5FU was given after GSK3B inhibition. Tissue microarray analysis of colon carcinoma samples from 5FU-treated patients revealed that GSK3B is significantly more activated in drug-resistant versus responsive patients.Conclusions: Targeting GSK3B, in combination with chemotherapy, may represent a novel strategy for the treatment of chemotherapy-resistant tumors.

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“…Western blot analysis showed that treatment with NVP-BEZ235 caused a sharp reduction in cyclin D1 protein levels in both the NCI-H720 and NCI-H727 cells, while everolimus reduced cyclin D1 protein levels in both the NCI-H720 and NCI-H727 cells to a smaller extent. It has been demonstrated previously that GSK3b activation promotes cyclin D1 degradation (Kunnimalaiyaan et al 2007). Figure 4C shows that both NVP-BEZ235 and everolimus are capable of reducing the phosphorylation levels of GSK3b at Ser 9 in both the NCI-H720 and NCI-H727 cells, indicating an increase in kinase activity of the enzyme (Martin et al 2005).…”

Section: Mtor Expression In Human Bc Cell Linesmentioning

confidence: 91%

mTOR, p70S6K, AKT, and ERK1/2 levels predict sensitivity to mTOR and PI3K/mTOR inhibitors in human bronchial carcinoids

Gagliano¹,

Bellio²,

Gentilin³

et al. 2013

Endocrine-Related Cancer

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Bronchial carcinoids (BCs) are rare neuroendocrine tumors that are still orphans of medical treatment. Human BC primary cultures may display resistance to everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), in terms of cell viability reduction. Our aim was to assess whether the novel dual phosphatidylinositol 3-kinase (PI3K)/mTOR inhibitor NVP-BEZ235 is effective in everolimus-resistant human BC tissues and cell lines. In addition, we searched for possible markers of the efficacy of mTOR inhibitors that may help in identifying the patients who may benefit from treatment with mTOR inhibitors, sparing them from ineffective therapy. We found that NVP-BEZ235 is twice as potent as everolimus in reducing cell viability and activating apoptosis in human BC tissues that display sensitivity to mTOR inhibitors, but is not effective in everolimus-resistant BC tissues and cell lines that bypass cyclin D1 downregulation and escape G0/G1 blockade. Rebound AKT activation was not observed in response to treatment with either mTOR inhibitor in the 'resistant' BC cells. In addition to total mTOR levels, putative markers of the sensitivity of BCs to mTOR inhibitors are represented by AKT, p70S6K (RPS6KB2), and ERK1/2 (MAPK3/1) protein levels. Finally, we validated these markers in an independent BC group. These data indicate that the dual PI3K/mTOR inhibitor NVP-BEZ235 is more potent than everolimus in reducing the proliferation of human BC cells. 'Resistant' cells display lower levels of mTOR, p70S6K, AKT, and ERK1/2, indicating that these proteins may be useful as predictive markers of resistance to mTOR and PI3K/mTOR inhibitors in human BCs.

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Inactivation of glycogen synthase kinase-3β, a downstream target of the raf-1 pathway, is associated with growth suppression in medullary thyroid cancer cells

Cited by 98 publications

References 37 publications

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

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

Inhibition of GSK3B Bypass Drug Resistance of p53-Null Colon Carcinomas by Enabling Necroptosis in Response to Chemotherapy

mTOR, p70S6K, AKT, and ERK1/2 levels predict sensitivity to mTOR and PI3K/mTOR inhibitors in human bronchial carcinoids

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