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Selective growth inhibition by glycogen synthase kinase-3 inhibitors in tumorigenic HeLa hybrid cells is mediated through NF-?B-dependent GLUT3 expression.

ABSTRACT: Carcinogenesis and cancer progression, driven by mutations in oncogenes and tumor-suppressor genes, result in biological differences between normal and cancer cells in various cellular processes. Specific genes and signaling molecules involved in such cellular processes may be potential therapeutic targets of agents that specifically interact with the key factors in cancer cells. Increased glucose uptake is fundamental to many solid tumors and well associated with increases in glycolysis and the overexpression of glucose transporters (GLUTs) such as GLUT1 and GLUT3 at the plasma membrane. Here, we used cell-based screening to identify glycogen synthase kinase-3? (GSK-3?) inhibitors that selectively target GLUT3-expressing tumorigenic HeLa cell hybrids as compared with non-tumorigenic hybrids that express GLUT1 alone. The GSK-3 inhibitors as well as GSK-3? RNAi suppressed GLUT3 expression at the level of transcription, leading to apoptosis. This suppression was associated with NF-?B in a p53-independent manner. Furthermore, GSK-3 inhibitors exhibited a synergistic effect with anticancer agents such as adriamycin and camptothecin in GULT3-overexpressing colon cancer cells, but little effect in non-producing A431 cells. These results suggest a potential use of GSK-3 inhibitors to selectively kill cancer cells that overexpress GLUT3.

SUBMITTER: Watanabe M

PROVIDER: S-EPMC3412655 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Selective growth inhibition by glycogen synthase kinase-3 inhibitors in tumorigenic HeLa hybrid cells is mediated through NF-κB-dependent GLUT3 expression.

Watanabe M M Abe N N Oshikiri Y Y Stanbridge E J EJ Kitagawa T T

Oncogenesis 20120709

Carcinogenesis and cancer progression, driven by mutations in oncogenes and tumor-suppressor genes, result in biological differences between normal and cancer cells in various cellular processes. Specific genes and signaling molecules involved in such cellular processes may be potential therapeutic targets of agents that specifically interact with the key factors in cancer cells. Increased glucose uptake is fundamental to many solid tumors and well associated with increases in glycolysis and the ...[more]

PMID: 23552737

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Project description: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.

Dataset Information

Selective growth inhibition by glycogen synthase kinase-3 inhibitors in tumorigenic HeLa hybrid cells is mediated through NF-?B-dependent GLUT3 expression.

Publications

Selective growth inhibition by glycogen synthase kinase-3 inhibitors in tumorigenic HeLa hybrid cells is mediated through NF-κB-dependent GLUT3 expression.

Similar Datasets

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