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, Tiebang Kang

Research output: Contribution to journalArticlepeer-review

99 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)749-763
Number of pages15
JournalJournal of the National Cancer Institute
Volume104
Issue number10
DOIs
StatePublished - May 16 2012

Bibliographical note

Funding Information:
This work was supported by grants from the National Natural Science Foundation of China (30872967 to JW, 30973504 to J-NS, 30930045 and 81125015 to TK), from Guangdong NSFC (8251008901000019 to J-NS and 10251008901000000 to TK), from the Ph.D. program foundation of the Ministry of Education of China (20060558018 to J-NS and 20100171110079 to TK) and from the 973 project (2010CB912201 and 2012CB967000 to TK).

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Glycogen synthase kinase-3β, NF-κB signaling, and tumorigenesis of human osteosarcoma'. Together they form a unique fingerprint.

Cite this