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Fine-tuning of NF?B by glycogen synthase kinase 3? directs the fate of glomerular podocytes upon injury.

ABSTRACT: Nuclear factor kappa-light-chain-enhancer of activated B cells (NF?B) is regulated by a myriad of signaling cascades including glycogen synthase kinase (GSK) 3? and plays a Janus role in podocyte injury. In vitro, lipopolysaccharide (LPS) or adriamycin (ADR) elicited podocyte injury and cytoskeletal disruption, associated with NF?B activation and induced expression of NF?B target molecules, including pro-survival Bcl-xL and podocytopathic mediators like MCP-1, cathepsin L, and B7-1. Broad-range inhibition of NF?B diminished the expression of all NF?B target genes, restored cytoskeleton integrity, but potentiated apoptosis. In contrast, blockade of GSK3? by lithium or 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) mitigated the expression of podocytopathic mediators, ameliorated podocyte injury, but barely affected Bcl-xL expression or sensitized apoptosis. Mechanistically, GSK3? was sufficient and essential for RelA/p65 phosphorylation, specifically at serine 467, which specifies the expression of selective NF?B target molecules, including podocytopathic mediators, but not Bcl-xL. In vivo, lithium or TDZD-8 therapy improved podocyte injury and proteinuria in mice treated with LPS or ADR, concomitant with the suppression of podocytopathic mediators, but retained Bcl-xL in glomerulus. Broad-range inhibition of NF?B conferred similar but much weakened antiproteinuric and podoprotective effects accompanied with a blunted glomerular expression of Bcl-xL and marked podocyte apoptosis. Thus, the GSK3?-dictated fine-tuning of NF?B may serve as a novel therapeutic target for podocytopathy.

SUBMITTER: Bao H

PROVIDER: S-EPMC4449834 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Fine-tuning of NFκB by glycogen synthase kinase 3β directs the fate of glomerular podocytes upon injury.

Bao Hui H Ge Yan Y Peng Ai A Gong Rujun R

Kidney international 20150128 6

Nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) is regulated by a myriad of signaling cascades including glycogen synthase kinase (GSK) 3β and plays a Janus role in podocyte injury. In vitro, lipopolysaccharide (LPS) or adriamycin (ADR) elicited podocyte injury and cytoskeletal disruption, associated with NFκB activation and induced expression of NFκB target molecules, including pro-survival Bcl-xL and podocytopathic mediators like MCP-1, cathepsin L, and B7-1. Broad-range ...[more]

PMID: 25629551

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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.

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Fine-tuning of NF?B by glycogen synthase kinase 3? directs the fate of glomerular podocytes upon injury.

Publications

Fine-tuning of NFκB by glycogen synthase kinase 3β directs the fate of glomerular podocytes upon injury.

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