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

Oncogene volume 29, pages 5989–6003 (2010)Cite this article

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Abstract

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′-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 α, interleukin (IL)-1α 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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Acknowledgements

This work was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM, U878), the Commissariat à l'Energie Atomique (iRTSV/LAPV), the Institut du Cancer (INCa, Program ‘Emergence des Cancéropoles 2004’), the Cancéropole Rhône-Alpes (CLARA) and the Groupement des Entreprises Françaises pour la Lutte contre le Cancer (GEFLUC)-Comité Dauphiné-Savoie. We also thank the Association pour la Recherche sur le Cancer and the Fondation pour la Recherche Médicale for their financial support to SP. We thank Dr Didier Grunwald (LTS, iRTSV, CEA-Grenoble) for helping us with the laser confocal microscopy platform of our institute. We also thank Dr Maryline Herbet and Dr Michael Thomas (INSERM U878, iRTSV, CEA-Grenoble) for their assistance in the ‘in vivo’ experiments and Dr Jean-Luc Coll (INSERM U883, UJF, Grenoble, France) for his generous gift of the LL/2-luciferase cell line.

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  1. Institut National de la Santé et de la Recherche Médicale, Grenoble, Rhône-Alpes, France

    S Planel, A Salomon, J-J Feige & N Cherradi

  2. Commissariat à l'Energie Atomique, Institut de Recherches en Technologies et Sciences pour le Vivant, LAPV, Grenoble, France

    S Planel, A Salomon, J-J Feige & N Cherradi

  3. Université Joseph Fourier, Grenoble, France

    S Planel, A Salomon, J-J Feige & N Cherradi

  4. LBMC/UMR5239 CNRS, ENS Lyon, Lyon, France

    P Jalinot

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  1. S Planel
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Correspondence to N Cherradi.

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Planel, S., Salomon, A., Jalinot, P. et al. A novel concept in antiangiogenic and antitumoral therapy: multitarget destabilization of short-lived mRNAs by the zinc finger protein ZFP36L1. Oncogene 29, 5989–6003 (2010). https://doi.org/10.1038/onc.2010.341

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