Tristetraprolin Down-regulates Interleukin-8 and Vascular Endothelial Growth Factor in Malignant Glioma Cells

Abstract

Malignant gliomas are highly aggressive tumors of the central nervous system that rely on production of growth factors for tumor progression. Vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), and tumor necrosis factor-A, for example, are up-regulated in these tumors to promote angiogenesis and proliferation. RNA stability, mediated through adenine and uridine-rich elements (ARE) in the 3 ¶ untranslated region, is a critical control point for regulating these growth factors. RNA half-life is predominantly governed by a balance between stabilizing and destabilizing factors that bind to ARE. We have previously shown that the stabilizing factor HuR is overexpressed in malignant gliomas and linked to RNA stabilization of angiogenic growth factors. Here, we report that the destabilizing factor tristetraprolin (TTP) is also ubiquitously expressed in primary malignant glioma tissues and cell lines. In contrast to benign astrogliotic tissues, however, the protein was hyperphosphorylated, with evidence implicating the p38/mitogen-activated protein kinase (MAPK) pathway. Conditional overexpression of TTP as a transgene in malignant glioma cells led to RNA destabilization of IL-8 and VEGF and down-regulation of protein production. Analysis of in vivo RNA binding indicated a shift of mRNA toward ectopic TTP and away from endogenous HuR. This biochemical phenotype was associated with a decrease in cell proliferation, loss of cell viability, and apoptosis. We postulate that hyperphosphorylation of TTP via p38/MAPK promotes progression of malignant gliomas by negatively regulating its RNA destabilizing function. [Cancer Res 2008;68(3):674-82]

ZFP36 expression impairs glioblastoma cell lines viability and invasiveness by targeting multiple signal transduction pathways

“…In the same cells, we also observed a necrotic cleavage of PARP-1 that further suggests that the ZFP36 induced cell death of ln827 GBM cells could depend on a necroptotic cell death program. Altogether, these data suggest that by restoring the expression of ZFP36, ln827 GBM cells die owing to the activation of two Moreover, there is evidence suggesting that ZFP36 is inactivated in gliomas, 17 and we collected further evidence (Fig. 1A) that in ln827 GBM cell lines, ZFP36 is expressed at very low levels.…”

“…15 As regards cancer biology, it has been shown that ZFP36 may alter the tumorigenic phenotype and patient prognosis, 16 probably targeting several oncogenes. ZFP36 is downregulated in many cancers, and, in particular, it has been shown that ZFP36 is hyperphosphorylated and therefore inactive in gliomas, 17 this leading to stabilization of VEGF and IL-8 mRNAs.…”

Characterization of LY2228820 Dimesylate, a Potent and Selective Inhibitor of p38 MAPK with Antitumor Activity

“…Ovarian cancer cells produce TNF-a and CXCL8 upon p38a MAPK activation, and these cytokines may act in an autocrine manner to promote peritoneal colonization and tumor vascularization (21). The U-87MG glioma, A-2780 and SK-OV-3 ovarian cancers, and PC3 prostate cancer all secrete VEGF, basic fibroblast growth factor (bFGF), EGF, and IL-6; and importantly, secretion of these cytokines can be significantly reduced by p38 MAPK inhibition (6,22). Furthermore, pretreatment of tumor cells with LY2228820 or p38a MAPK short hairpin RNA (shRNA) reduces cord formation in a tumor/adipocyte-derived stem/endothelial colony-forming cell coculture system, supporting a p38 MAPK-mediated effect of the tumor on the TME (6).…”

Tristetraprolin Inhibits the Growth of Human Glioma Cells through Downregulation of Urokinase Plasminogen Activator/Urokinase Plasminogen Activator Receptor mRNAs

“…Moreover, a lack of TTP is associated with a variety of cancer-related processes (Brennan et al, 2009). In this respect, regulation of TTP expression has been shown to play a role in several cancers such as colon, breast, skin, lung, and brain (Lee et al, 2013;Suswam et al, 2008). However, its role in glioma has not been fully investigated.…”