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Glycogen synthase kinase-3?, NF-?B signaling, and tumorigenesis of human osteosarcoma.

ABSTRACT: Glycogen synthase kinase-3? (GSK-3?), 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-3? in osteosarcoma, a rare pediatric cancer for which the identification of new therapeutic targets is urgent.We used cell viability assays, colony formation assays, and apoptosis assays to analyze the effects of altered GSK-3? 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-3? 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-3? inhibition on the nuclear factor-?B (NF-?B) pathway. Immunochemistry was performed on primary tumor specimens from osteosarcoma patients (n = 74) to determine the relationship of GSK-3? activity with overall survival.Osteosarcoma cells with low levels of inactive p-Ser9-GSK-3? formed colonies in vitro and tumors in vivo more readily than cells with higher levels and cells in which GSK-3? had been silenced formed fewer colonies and smaller tumors than parental cells. Silencing or pharmacological inhibition of GSK-3? resulted in apoptosis of osteosarcoma cells. Inhibition of GSK-3? resulted in inhibition of the NF-?B pathway and reduction of NF-?B-mediated transcription. Combination treatments with GSK-3? inhibitors, NF-?B inhibitors, and chemotherapy drugs increased the effectiveness of chemotherapy drugs in vitro and in vivo. Patients whose osteosarcoma specimens had hyperactive GSK-3?, and nuclear NF-?B had a shorter median overall survival time (49.2 months) compared with patients whose tumors had inactive GSK-3? and NF-?B (109.2 months).GSK-3? activity may promote osteosarcoma tumor growth, and therapeutic targeting of the GSK-3? and/or NF-?B pathways may be an effective way to enhance the therapeutic activity of anticancer drugs against osteosarcoma.

SUBMITTER: Tang QL

PROVIDER: S-EPMC3352834 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Glycogen synthase kinase-3β, NF-κB signaling, and tumorigenesis of human osteosarcoma.

Tang Qing-Lian QL Xie Xian-Biao XB Wang Jin J Chen Qiong Q Han An-Jia AJ Zou Chang-Ye CY Yin Jun-Qiang JQ Liu Da-Wei DW Liang Yi Y Zhao Zhi-Qiang ZQ Yong Bi-Cheng BC Zhang Ru-Hua RH Feng Qi-Sheng QS Deng Wu-Guo WG Zhu Xiao-Feng XF Zhou Binhua P BP Zeng Yi-Xin YX Shen Jing-Nan JN Kang Tiebang T

Journal of the National Cancer Institute 20120424 10

<h4>Background</h4>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.<h4>Methods</h4>We used cell viability assays, colony formation assays, and apoptosis assays to analyze the effects of altered GSK-3β expression in U2OS, MG63, SAOS ...[more]

PMID: 22534782

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Project description:A number of studies have attempted to elucidate the association between mircoRNAs (miRNAs/miRs) and cancer-associated processes. The aim of the present study was to determine how miR-499a-5p intervenes in human osteosarcoma cell proliferation and differentiation. The cancerous tissues and adjacent non-cancerous tissues of 62 patients with osteosarcoma (OS) were collected. miRNA microarray analysis revealed that 29 miRNAs were upregulated while 26 were downregulated, among which miR-499a-5p expression was the most decreased. Western blot analysis and reverse transcription-quantitative polymerase chain reaction demonstrated that the mRNA and protein expression of miR-499a-5p was lower, while that of protein phosphatase 1D (PPM1D) was higher in OS tissues compared with expression levels in normal tissues. Furthermore, miR-499a-5p expression was markedly decreased in the metastatic tumors and in those at stage III+IV compared with the non-metastatic tumors and those at stage I, respectively. In addition, following transfection of the human OS MG-63 cell line with an miR-499a-5p mimic, the expression of miR-499a-5p was elevated while the protein and mRNA expression of PPM1D was decreased. When combining these findings with the information obtained from the Targetscan predictive software, it was confirmed that PPM1D was targeted by miR-499a-5p. In MG-63 cells transfected with an miR-499a-5p mimic, PPM1D-associated downstream proteins phosphorylated protein kinase B (p-Akt) and phosphorylated glycogen synthase kinase 3β (p-GSK-3β) were significantly downregulated compared with the negative control (NC) group, while the expression of p-Akt and p-GSK-3β were significantly elevated in the tumor tissues compared with the adjacent non-tumor tissues. Simultaneously, the growth and proliferation activity of MG-63 cells were notably reduced when transfected with the miR-499a-5p mimic, compared with the NC group. Therefore, it may be concluded that miR-499a-5p suppresses OS cell proliferation and differentiation by targeting PPM1D through modulation of Akt/GSK-3β signaling.

Dataset Information

Glycogen synthase kinase-3?, NF-?B signaling, and tumorigenesis of human osteosarcoma.

Publications

Glycogen synthase kinase-3β, NF-κB signaling, and tumorigenesis of human osteosarcoma.

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