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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2009-11-17

AUTHORS

V Bilim, A Ougolkov, K Yuuki, S Naito, H Kawazoe, A Muto, M Oya, D Billadeau, T Motoyama, Y Tomita

ABSTRACT

Background:Renal cell carcinoma (RCC) is highly resistant to chemotherapy because of a high apoptotic threshold. Recent evidences suggest that GSK-3β positively regulates human pancreatic cancer and leukaemia cell survival in part through regulation of nuclear factor (NF-κB)-mediated expression of anti-apoptotic molecules. Our objectives were to determine the expression pattern of GSK-3β and to assess the anti-cancer effect of GSK-3β inhibition in RCC.Methods:Immunohistochemistry and nuclear/cytosolic fractionation were performed to determine the expression pattern of GSK-3β 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-3β inactivation on renal cancer cell proliferation and survival.Results:We detected aberrant nuclear accumulation of GSK-3β 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-κB 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-3β 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. More... »

PAGES

2005-2014

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/sj.bjc.6605437

DOI

http://dx.doi.org/10.1038/sj.bjc.6605437

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1016108440

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/19920820


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34 schema:description Background:Renal cell carcinoma (RCC) is highly resistant to chemotherapy because of a high apoptotic threshold. Recent evidences suggest that GSK-3β positively regulates human pancreatic cancer and leukaemia cell survival in part through regulation of nuclear factor (NF-κB)-mediated expression of anti-apoptotic molecules. Our objectives were to determine the expression pattern of GSK-3β and to assess the anti-cancer effect of GSK-3β inhibition in RCC.Methods:Immunohistochemistry and nuclear/cytosolic fractionation were performed to determine the expression pattern of GSK-3β 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-3β inactivation on renal cancer cell proliferation and survival.Results:We detected aberrant nuclear accumulation of GSK-3β 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-κB 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-3β 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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41 BrdU incorporation
42 GSK-3
43 GSK-3 inhibitors
44 GSK-3 results
45 GSK-3β
46 GSK-3β inactivation
47 GSK-3β inhibition
48 MTS
49 NF
50 RCC cell lines
51 RCC cell survival
52 RNA interference
53 RT-PCR
54 Recent evidence
55 Western blotting
56 XIAP
57 aberrant nuclear accumulation
58 accumulation
59 anti-apoptotic molecules
60 anti-cancer effects
61 apoptosis
62 apoptotic threshold
63 approach
64 blotting
65 cancer
66 cancer cell apoptosis
67 cancer cell proliferation
68 cancer cells
69 carcinoma
70 cell apoptosis
71 cell carcinoma
72 cell lines
73 cell proliferation
74 cell survival
75 cells
76 chemotherapy
77 cytosolic fractionation
78 decrease
79 decreased expression
80 docetaxel
81 effect
82 evidence
83 expression
84 expression patterns
85 factors
86 fractionation
87 gene Bcl-2
88 high apoptotic threshold
89 human pancreatic cancer
90 human renal cancer
91 human renal cell carcinoma
92 immunohistochemistry
93 inactivation
94 incorporation
95 increase
96 inhibition
97 inhibitors
98 interference
99 leukemia cell survival
100 lines
101 markers
102 molecule inhibitors
103 molecules
104 new markers
105 new promising approach
106 new therapeutic targets
107 nuclear accumulation
108 nuclear factor
109 objective
110 pancreatic cancer
111 part
112 patterns
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115 promising approach
116 quantitative RT-PCR
117 regulation
118 renal cancer
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121 renal cancer cells
122 renal cell carcinoma
123 results
124 small molecule inhibitors
125 subsequent increase
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127 survival
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129 target genes Bcl-2
130 therapeutic target
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