title: A novel concept in antiangiogenic and antitumoral therapy: multitarget destabilization of short-lived mRNAs by the zinc finger protein ZFP36L1.
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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Grenoble, Rhône-Alpes, France.
authors.forename: S
authors.initials: S
authors.lastname: Planel
authors.forename: A
authors.initials: A
authors.lastname: Salomon
authors.forename: P
authors.initials: P
authors.lastname: Jalinot
authors.forename: J-J
authors.initials: JJ
authors.lastname: Feige
authors.forename: N
authors.initials: N
authors.lastname: Cherradi
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D051817:Butyrate Response Factor 1 / Q000494:pharmacology*; D019556:COS Cells; D018827:Carcinoma, Lewis Lung; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000037:antagonists & inhibitors; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D017434:Protein Structure, Tertiary; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000187:drug effects*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D051817:Butyrate Response Factor 1; D016207:Cytokines; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A; C102034:ZFP36L1 protein, human