Tristetraprolin Inhibits Ras-dependent Tumor Vascularization by Inducing Vascular Endothelial Growth Factor mRNA Degradation

Essafi‐Benkhadir, Khadija; Onesto, Cercina; E, Stebe; Moroni, Christoph; Pagès, Gilles

doi:10.1091/mbc.e07-06-0570

Cited by 92 publications

(105 citation statements)

References 42 publications

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“…Moreover, CXCL8 could indirectly stimulate VEGF production by 786-O cells as they express the CXCR-2 receptor (Mestas et al, 2005). Stimulation of CXCR-2 induces the activation of the ERK pathway, which could stimulate VEGF gene transcription and increase VEGF mRNA stability (Milanini et al, 1998;Essafi-Benkhadir et al, 2007).Increased production of CXCL in vitro or in the tumor context following BVZ treatment may be explained by a direct action of VEGFxxx on 786-O cells. This result suggests that RCC cells should express the VEGF receptor(s).…”

Section: Discussionmentioning

confidence: 99%

“…Tumor sections were handled as described previously (Essafi-Benkhadir et al, 2007). Sections were incubated with anti-mouse LYVE-1 polyclonal (Ab 14817, 1:200; Abcam, Cambridge, MA, USA) or monoclonal anti-a-smooth muscle actin Sigma (A2547, 1:1000; Sigma, France), and rat monoclonal anti-mouse CD31 (clone MEC 13.3, 1:1000; BD Pharmingen, Franklin Lakes, NJ, USA) antibodies.…”

Section: Immunofluorescence Experimentsmentioning

confidence: 99%

“…Four hours after transfection BVZ was added (or not) to the cell culture medium at a concentration of 500 ng/ml. Luciferase assays were performed as described previously (Essafi-Benkhadir et al, 2007).…”

Section: Plasmid Transfectionmentioning

confidence: 99%

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Acceleration of clear cell renal cell carcinoma growth in mice following bevacizumab/Avastin treatment: the role of CXCL cytokines

et al. 2011

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The anti-VEGF targeted antibody bevacizumab (BVZ) has been approved for treating renal cell carcinomas (RCCs). Although BVZ increases the progression-free survival of patients with metastatic RCC, the effect on overall survival is poor. To gain insight into the limited efficacy of BVZ on overall survival, we analyzed patient samples of RCC for angiogenic factors that may participate in escape from anti-VEGF therapy. Our study shows that the level of vascular endothelial growth factor (VEGF) in tumors was increased compared with normal tissue. The level of interleukin-8/ CXCL8, a pro-angiogenic member of the CXCL family of cytokines, was also increased in tumors. These observations gave us a good reason to analyze the combined effects of BVZ and anti-CXCL8 antibodies on tumor growth. Surprisingly, we report that BVZ accelerates the growth of RCC in nude mice with in vivo selection of tumor cells with an increased growth capacity. Downregulation of receptor tyrosine phosphatase-j, a phosphatase implicated in EGF receptor regulation, may partly explain this phenomenon. Modification of the vascular network and development of lymphatic vessels through VEGF-C production and compensatory production of pro-angiogenic CXCL cytokines were also observed. The apparent normalization of the vascular network prompted us to associate BVZ with the chemotherapeutic agent paclitaxel. While efficient in vitro, paclitaxel did not reverse the anti-VEGF effects in vivo. Anti-CXCL8-targeting antibodies were promising as they decreased intra-tumor VEGF production; decreased the pro-angiogenic CXCL/anti-angiogenic CXCL ratio and did not induce lymphangiogenesis. These observations hold clinical implication as they highlight putative markers implicated in escape from BVZ treatment. They also recommend proceeding with caution in the use of anti-VEGF therapy alone for treatment of RCC.

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Section: Discussionmentioning

confidence: 99%

Section: Immunofluorescence Experimentsmentioning

confidence: 99%

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Acceleration of clear cell renal cell carcinoma growth in mice following bevacizumab/Avastin treatment: the role of CXCL cytokines

et al. 2011

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“…5A). TTP can control cell growth through destabilization of c-fos, c-myc, and cyclin D 1 mRNAs (30,34) and VEGF and COX-2 mRNAs (32,(35)(36)(37). To determine whether a reduced expression level of TTP affects the expression of these genes, we tested the changes in the expression levels of these genes in A549 cells by semiquantitative RT-PCR (Fig.…”

Section: Cells (D and F) Expression Of Ttp And Lats2 Was Determined mentioning

confidence: 99%

Stability of the LATS2 Tumor Suppressor Gene Is Regulated by Tristetraprolin

Lee

Kim

et al. 2010

Journal of Biological Chemistry

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LATS2 is a tumor suppressor gene implicated in the control of cell growth and the cell cycle. Here, we investigated the posttranscriptional regulation of LATS2 expression by tristetraprolin (TTP). Our results show that the expression level of LATS2 is inversely correlated with TTP expression in human cancer cell lines. Overexpression of TTP reduced the expression level of LATS2. Conversely, treatment with small interfering RNA against TTP increased the expression level of LATS2 through stabilization of LATS2 mRNA and suppressed the proliferation of A549 human lung cancer cells. LATS2 mRNA contains AUrich elements (AREs) within the 3-untranslated region, and TTP destabilized a luciferase mRNA containing LATS2 ARE. In addition, RNA electrophoretic mobility shift assay revealed that TTP directly bound to the ARE of LATS2 mRNA. These results establish LATS2 mRNA as a physiological target of TTP and suggest the possibility that TTP controls cell growth through regulation of LATS2 mRNA stability.LATS2 is a new member of the LATS tumor suppressor family (1-3). The LATS2 gene is located at chromosome 13q11-12 and encodes a 1046-amino acid protein that contains a C-terminal serine/threonine kinase domain (4). According to recent publications, LATS2 appears to coordinate the cell cycle, cell proliferation, and cell death. LATS2 promotes the stabilization of p53 by inactivating MDM2 (5), plays a role in maintenance of mitotic fidelity (6), and regulates spindle organization through recruitment of ␥-tubulin to the centrosome (7). Overexpression of LATS2 results in G 2 /M arrest via inhibition of Cdc2 kinase activity (8), inhibition of G 1 /S transition via down-regulation of cyclin E/Cdk2 kinase activity (9), and induction of apoptosis via down-regulation of apoptotic inhibitors such as Bcl-2 and Bcl-x L (10). Deletion of LATS2 in flies (11, 12) and mice (13) accelerates cell proliferation and tumor development, indicating that the reduced function of the LATS2 gene leads to accelerated cell proliferation.Expression of LATS2 is down-regulated in several human cancer cells (14 -18). The mechanisms for down-regulation have been the subject of substantial interest. It has been reported that the expression of LATS2 in breast cancer (14), astrocytoma (17), and acute lymphoblastic leukemia (18, 19) is down-regulated by hypermethylation of the promoter. In addition, LATS2 mRNA is down-regulated at the post-transcriptional level by microRNA-372 and microRNA-373 in testicular germ cell tumors (20), gastric cancer cells (21), and esophageal cancer cells (22), suggesting that the expression of the LATS2 gene is controlled at the post-transcriptional level as well as the transcriptional level.Post-transcriptional regulation of gene expression is also mediated by AU-rich elements (AREs) 4 located in the 3Ј-untranslated region (3Ј-UTR) of a variety of short-lived mRNAs such as cytokines and proto-oncogenes (23). The destabilizing function of AREs is believed to be regulated by ARE-binding proteins (24). Numerous ARE-binding proteins ha...

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“…TTP, the most studied member of ZFP36L1 family has been reported to act as a potent tumor suppressor when overexpressed in a v-Hras-expressing IL-3-dependent mast cells (Stoecklin et al, 2003). More recently, Essafi-Benkhadir et al (2007) reported that TTP overexpression inhibits RasVal12-dependent tumor vascularization by inducing VEGF mRNA degradation. Whereas transfection experiments yield highly significant information concerning the emerging link between mRNA stability and cancer, inherent limitations of transgenic technologies impede their potential use in human disease therapies.…”

Section: Discussionmentioning

confidence: 99%

A novel concept in antiangiogenic and antitumoral therapy: multitarget destabilization of short-lived mRNAs by the zinc finger protein ZFP36L1

et al. 2010

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Angiogenesis inhibitors have shown clinical benefits in patients with advanced cancer, but further therapeutic improvement is needed. We have previously shown that the zinc finger protein 36, C3H type-like 1 (ZFP36L1) enhances vascular endothelial growth factor (VEGF) mRNA decay through its interaction with AU-rich elements within VEGF 3 0 -untranslated region. In this study, we evaluated the possibility to develop an antiangiogenic and antitumoral strategy using the mRNA-destabilizing activity of ZFP36L1. We engineered a cell-penetrating ZFP36L1, by fusing it to the protein transduction domains (PTDs) TAT derived from HIV, or the polyarginine peptides R7 or R9. PTD-ZFP36L1 fusion proteins were expressed in bacterial cells and affinity-purified to homogeneity. TAT-, R7-and R9-ZFP36L1 were efficiently internalized into living cells and decreased both endogenous VEGF mRNA half-life and VEGF protein levels in vitro. Importantly, a single injection of R9-TIS11b fusion protein into a high-VEGF expressing tissue in vivo (in this study, the mouse adrenal gland) markedly decreased VEGF expression. We further evaluated the effect of R9-ZFP36L1 on tumor growth using Lewis Lung Carcinoma (LL/2) cells implanted subcutaneously into nude mice. Intratumoral injection of R9-ZFP36L1 significantly reduced tumor growth and markedly decreased the expression of multiple angiogenic and inflammatory cytokines, including VEGF, acidic fibroblast growth factor, tumor necrosis factor a, interleukin (IL)-1a and IL-6, with a concomitant obliteration of tumor vascularization. These findings indicate that R9-ZFP36L1 fusion protein may represent a novel antiangiogenic and antitumoral agent, and supports the emerging idea that modulation of mRNA stability represents a promising therapeutic approach to treat cancer.

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Tristetraprolin Inhibits Ras-dependent Tumor Vascularization by Inducing Vascular Endothelial Growth Factor mRNA Degradation

Cited by 92 publications

References 42 publications

Acceleration of clear cell renal cell carcinoma growth in mice following bevacizumab/Avastin treatment: the role of CXCL cytokines

Acceleration of clear cell renal cell carcinoma growth in mice following bevacizumab/Avastin treatment: the role of CXCL cytokines

Stability of the LATS2 Tumor Suppressor Gene Is Regulated by Tristetraprolin

A novel concept in antiangiogenic and antitumoral therapy: multitarget destabilization of short-lived mRNAs by the zinc finger protein ZFP36L1

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