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SOD3 improves the tumor response to chemotherapy by stabilizing endothelial HIF-2α.

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2018

Nat Commun 2018 Feb 8;9(1):575. doi: 10.1038/s41467-018-03079-1.

SOD3 improves the tumor response to chemotherapy by stabilizing endothelial HIF-2α.

E Mira;L Carmona-Rodríguez;B Pérez-Villamil;J Casas;MJ Fernández-Aceñero;D Martínez-Rey;P Martín-González;I Heras-Murillo;M Paz-Cabezas;M Tardáguila;TD Oury;S Martín-Puig;RA Lacalle;G Fabriás;E Díaz-Rubio;S Mañes

Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Darwin, 3, Madrid, 28049, Spain. Genomics and Microarray Laboratory, Medical Oncology & Surgical Pathology Departments, Instituto de Investigación Sanitaria San Carlos Hospital Clínico San Carlos, Univ. Complutense de Madrid, CIBERONC, Profesor Martín Lagos, S/N, Madrid, 28040, Spain. Department of Biomedicinal Chemistry, Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), Jordi Girona 18-26, Barcelona, 08034, Spain. Genetics Institute, University of Florida, 2033 Mowry Road, Gainesville, FL, 32610, USA. Department of Pathology, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA, 15261, USA. Myocardial Pathophysiology Area, Centro Nacional de Investigaciones Cardiovasculares, Calle de Melchor Fernández Almagro, 3, Madrid, 28029, Spain.

Service type: Transgenic mice

Abstract

One drawback of chemotherapy is poor drug delivery to tumor cells, due in part to hyperpermeability of the tumor vasculature. Extracellular superoxide dismutase (SOD3) is an antioxidant enzyme usually repressed in the tumor milieu. Here we show that specific SOD3 re-expression in tumor-associated endothelial cells (ECs) increases doxorubicin (Doxo) delivery into and chemotherapeutic effect on tumors. Enhanced SOD3 activity fostered perivascular nitric oxide accumulation and reduced vessel leakage by inducing vascular endothelial cadherin (VEC) transcription. SOD3 reduced HIF prolyl hydroxylase domain protein activity, which increased hypoxia-inducible factor-2α (HIF-2α) stability and enhanced its binding to a specific VEC promoter region. EC-specific HIF-2α ablation prevented both the SOD3-mediated increase in VEC transcription and the enhanced Doxo effect. SOD3, VEC, and HIF-2α levels correlated positively in primary colorectal cancers, which suggests a similar interconnection of these proteins in human malignancy.

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