Journal Article

Glycogen Synthase Kinase-3β, NF-κB Signaling, and Tumorigenesis of Human Osteosarcoma

Qing-Lian Tang, Xian-Biao Xie, Jin Wang, Qiong Chen, An-Jia Han, Chang-Ye Zou, Jun-Qiang Yin, Da-Wei Liu, Yi Liang, Zhi-Qiang Zhao, Bi-Cheng Yong, Ru-Hua Zhang, Qi-Sheng Feng, Wu-Guo Deng, Xiao-Feng Zhu, Binhua P. Zhou, Yi-Xin Zeng, Jing-Nan Shen and Tiebang Kang

in JNCI: Journal of the National Cancer Institute

Published on behalf of National Cancer Institute

Volume 104, issue 10, pages 749-763
Published in print May 2012 | ISSN: 0027-8874
Published online April 2012 | e-ISSN: 1460-2105 | DOI: http://dx.doi.org/10.1093/jnci/djs210

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Background

Glycogen synthase kinase-3β (GSK-3β), a serine/threonine protein kinase, may function as a tumor suppressor or an oncogene, depending on the tumor type. We sought to determine the biological function of GSK-3β in osteosarcoma, a rare pediatric cancer for which the identification of new therapeutic targets is urgent.

Methods

We used cell viability assays, colony formation assays, and apoptosis assays to analyze the effects of altered GSK-3β expression in U2OS, MG63, SAOS2, U2OS/MTX300, and ZOS osteosarcoma cell lines. Nude mice (n = 5–8 mice per group) were injected with U2OS/MTX300, and ZOS cells to assess the role of GSK-3β in osteosarcoma growth in vivo and to evaluate the effects of inhibitors and/or anticancer drugs on tumor growth. We used an antibody array, polymerase chain reaction, western blotting, and a luciferase reporter assay to establish the effect of GSK-3β inhibition on the nuclear factor-κB (NF-κB) pathway. Immunochemistry was performed on primary tumor specimens from osteosarcoma patients (n = 74) to determine the relationship of GSK-3β activity with overall survival.

Results

Osteosarcoma cells with low levels of inactive p-Ser9-GSK-3β formed colonies in vitro and tumors in vivo more readily than cells with higher levels and cells in which GSK-3β had been silenced formed fewer colonies and smaller tumors than parental cells. Silencing or pharmacological inhibition of GSK-3β resulted in apoptosis of osteosarcoma cells. Inhibition of GSK-3β resulted in inhibition of the NF-κB pathway and reduction of NF-κB-mediated transcription. Combination treatments with GSK-3β inhibitors, NF-κB inhibitors, and chemotherapy drugs increased the effectiveness of chemotherapy drugs in vitro and in vivo. Patients whose osteosarcoma specimens had hyperactive GSK-3β, and nuclear NF-κB had a shorter median overall survival time (49.2 months) compared with patients whose tumors had inactive GSK-3β and NF-κB (109.2 months).

Conclusion

GSK-3β activity may promote osteosarcoma tumor growth, and therapeutic targeting of the GSK-3β and/or NF-κB pathways may be an effective way to enhance the therapeutic activity of anticancer drugs against osteosarcoma.

Journal Article.  10167 words.  Illustrated.

Subjects: Medical Oncology

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