Suppression of tumor growth via IGFBP3 depletion as a potential treatment in glioma

Abstract

OBJECTIVEDespite intensive medical treatment, patients with glioblastoma (grade IV glioma [GBM]) have a low 5-year survival rate of 5.5%. In this study, the authors tried to improve currently used therapies by identification of a therapeutic target, IGFBP3, for glioma treatment.METHODSIGFBP3 RNA expression in 135 patients newly diagnosed with glioma was correlated with clinicopathological factors. Immunohistochemical analysis was performed to determine IGFBP3 protein expression in glioma specimens. The effect of IGFBP3 depletion on cell proliferation was examined using IGFBP3 knockdown glioma cells. Intracranial infusion of IGFBP3 siRNAs was performed to evaluate the effect of IGFBP3 depletion in mouse intracranial xenograft models.RESULTSWe demonstrated higher IGFBP3 expression in GBM than in tumor margin and grade II glioma. IGFBP3 expression was not only positively correlated with tumor grades but also associated with tumor histology and IDH1/2 mutation status. Additionally, higher IGFBP3 expression predicted shorter overall survival in glioma and GBM proneural subgroup patients. In vitro cell culture studies suggested IGFBP3 knockdown suppressed cell proliferation and induced cell cycle G2/M arrest as well as apoptosis in glioma cells. Also, accumulation of DNA double-strand breaks and γH2AX was observed in IGFBP3 knockdown cells. IGFBP3 knockdown delayed in vivo tumor growth in mouse subcutaneous xenograft models. Furthermore, convection-enhanced delivery of IGFBP3 siRNA to mouse brain suppressed intracranial tumor growth and prolonged survival of tumor-bearing mice.CONCLUSIONSOur findings suggest IGFBP3 predicts poor outcome of glioma patients and is a potential therapeutic target for which depletion of its expression suppresses tumor growth through inducing apoptosis and accumulation of DNA damage in glioma cells.

Ras-AKT signaling represses the phosphorylation of histone H1.5 at threonine 10 via GSK3 to promote the progression of glioma

“…Like CYR61, overexpression of WNT16B promoted tumor growth and chemotherapy resistance [26]. Depletion of IGFBP3 [27] or NT5E [28] induced tumor cell loss and thereby suppressed tumor cells growth. Of contrast, in vitro and in vivo experiments suggested overexpression of GDF15 [29] or CARD16 [30] inhibited tumor cell growth via controlling caspases and cell proliferation, respectively.…”

IRE1α and IGF signaling predict resistance to an endoplasmic reticulum stress-inducing drug in glioblastoma cells

“…Remarkably, transcriptional profiling and network analysis of R vs. NR neurosphere lines identified additional differentially-expressed gene networks. Within these, two genes, IGFBP3 and IGFBP5, belonging to the IGF-1 signaling pathway, have been previously implicated in tumorigenesis 36,37 including GBM 38 . IGFBPs can drive tumorigenesis by increasing IGF-dependent signaling that in turn increases cancer cell proliferation and survival 39 .…”

Prognostic and Therapeutic Roles of the Insulin Growth Factor System in Glioblastoma

“…The tumor promoting properties of IGFBP-3 are linked to its ability to increase STAT-1 expression that, in turn, result associated with reduced patients overall survival (OS) ( 57 ). Furthermore, Chia-Hua Chen demonstrated that IGFBP-3 silencing suppresses glioma cell proliferation by G2/M cell cycle arrest ( 58 ). On the contrary, the anti-tumorigenic and anti-angiogenetic functions of IGFBP-4 in glioma cells depend to its ability to induce dibutyryl cyclic AMP (dB-cAMP) that antagonize the VEGFs action in an IGF-independent manner ( 59 ).…”