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

被引：94

作者：

Bilim, V. ^{[1
]}

Ougolkov, A. ^{[2
]}

Yuuki, K. ^{[1
]}

Naito, S. ^{[1
]}

Kawazoe, H. ^{[1
]}

Muto, A. ^{[1
]}

Oya, M. ^{[3
]}

Billadeau, D. ^{[4
]}

Motoyama, T. ^{[5
]}

Tomita, Y. ^{[1
]}

机构：

[1] Yamagata Univ, Sch Med, Dept Urol, Yamagata 9909585, Japan

[2] Northwestern Univ, Dept Pathol, Feinberg Sch Med, Chicago, IL 60611 USA

[3] Keio Univ, Sch Med, Dept Urol, Shinjuku Ku, Tokyo, Japan

[4] Mayo Clin, Coll Med, Div Oncol Res, Rochester, MN 55905 USA

[5] Yamagata Univ, Sch Med, Dept Pathol 2, Dept Human Pathol, Yamagata 9909585, Japan

来源：

BRITISH JOURNAL OF CANCER | 2009年 / 101卷 / 12期

关键词：

renal cell carcinoma; apoptosis; glycogen synthase kinase-3 beta; FACTOR-KAPPA-B; CANCER-CELLS; PANCREATIC-CANCER; GENE-TRANSCRIPTION; INDUCED APOPTOSIS; PROSTATE-CANCER; INHIBITION; SURVIVAL; PROLIFERATION; ACTIVATION;

D O I：

10.1038/sj.bjc.6605437

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

BACKGROUND: Renal cell carcinoma (RCC) is highly resistant to chemotherapy because of a high apoptotic threshold. Recent evidences suggest that GSK-3 beta positively regulates human pancreatic cancer and leukaemia cell survival in part through regulation of nuclear factor (NF-kappa B)-mediated expression of anti-apoptotic molecules. Our objectives were to determine the expression pattern of GSK-3 beta and to assess the anti-cancer effect of GSK-3 beta inhibition in RCC. METHODS: Immunohistochemistry and nuclear/cytosolic fractionation were performed to determine the expression pattern of GSK-3 beta 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-3 beta inactivation on renal cancer cell proliferation and survival. RESULTS: We detected aberrant nuclear accumulation of GSK-3 beta 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-kappa B 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-3 beta 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. British Journal of Cancer (2009) 101, 2005-2014. doi: 10.1038/sj.bjc.6605437 www.bjcancer.com Published online 17 November 2009 (C) 2009 Cancer Research UK

引用

页码：2005 / 2014

页数：10

共 36 条

[31] Glycogen synthase kinase 3β functions to specify gene-specific, NF-κB-dependent transcription [J].

Steinbrecher, KA ;

Wilson, W ;

Cogswell, PC ;

Baldwin, AS .

MOLECULAR AND CELLULAR BIOLOGY, 2005, 25 (19) :8444-8455

[32] Lithium suppresses cell proliferation by interrupting E2F-DNA interaction and subsequently reducing S-phase gene expression in prostate cancer [J].

Sun, Aijing ;

Shanmugam, Ilanchezian ;

Song, Jiawu ;

Terranova, Paul F. ;

Thrasher, J. Brantley ;

Li, Benyi .

PROSTATE, 2007, 67 (09) :976-988

[33]

Tomita Y, 1996, INT J CANCER, V66, P322, DOI 10.1002/(SICI)1097-0215(19960503)66:3<322::AID-IJC9>3.0.CO

[34]

2-0

[35] Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy [J].

Wang, Zhong ;

Smith, Kevin S. ;

Murphy, Mark ;

Piloto, Obdulio ;

Somervaille, Tim C. P. ;

Cleary, Michael L. .

NATURE, 2008, 455 (7217) :1205-U29

[36] Maintenance of constitutive IκB kinase activity by glycogen synthase kinase-3α/β in pancreatic cancer [J].

Wilson, Willie, III ;

Baldwin, Albert S. .

CANCER RESEARCH, 2008, 68 (19) :8156-8163

← 1 2 3 4 →