Selective targeting of collagen IV in the cancer cell microenvironment reduces tumor burden
| Autor: | Ana Díaz, Ignacio Ventura, Aida Artigot, Javier Alcácer, Fernando Revert, Nuria Roda, Enrique Pérez-Payá, Juan F. Sanz-Cervera, Ernesto López-Pascual, Elain Gutierrez-Carbonell, Alejandra Maria Pérez-Sastre, Juan Saus, Roberto Gozalbo-Rovira, Daniel Ruíz-Sanchis, Raúl Mínguez Blasco, Francisco Revert-Ros, Jerónimo Forteza |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Tumor microenvironment Chemistry Kinase Mesenchymal stem cell EMT Phenotype 03 medical and health sciences 030104 developmental biology Oncology GPBP Precursor cell Cancer cell Cancer research medicine collagen IV tumor microenvironment Doxorubicin Secretion drug-resistant cancer medicine.drug Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | Goodpasture antigen-binding protein (GPBP) is an exportable1 Ser/Thr kinase that induces collagen IV expansion and has been associated with chemoresistance following epithelial-to-mesenchymal transition (EMT). Here we demonstrate that cancer EMT phenotypes secrete GPBP (mesenchymal GPBP) which displays a predominant multimeric oligomerization and directs the formation of previously unrecognized mesh collagen IV networks (mesenchymal collagen IV). Yeast two-hybrid (YTH) system was used to identify a 260SHCIE264 motif critical for multimeric GPBP assembly which then facilitated design of a series of potential peptidomimetics. The compound 3-[4''-methoxy-3,2'-dimethyl-(1,1';4',1'')terphenyl-2''-yl]propionic acid, or T12, specifically targets mesenchymal GPBP and disturbs its multimerization without affecting kinase catalytic site. Importantly, T12 reduces growth and metastases of tumors populated by EMT phenotypes. Moreover, low-dose doxorubicin sensitizes epithelial cancer precursor cells to T12, thereby further reducing tumor load. Given that T12 targets the pathogenic mesenchymal GPBP, it does not bind significantly to normal tissues and therapeutic dosing was not associated with toxicity. T12 is a first-in-class drug candidate to treat cancer by selectively targeting the collagen IV of the tumor cell microenvironment. |
| Databáze: | OpenAIRE |
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