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

Emilia Mira, Lorena Carmona-Rodríguez, Beatriz Pérez-Villamil, Josefina Casas, María Jesús Fernández-Aceñero, Diego Martínez-Rey, Paula Martín-González, Ignacio Heras-Murillo, Mateo Paz-Cabezas, Manuel Tardáguila, Tim D. Oury, Silvia Martín-Puig, Rosa Ana Lacalle, Gemma Fabriás, Eduardo Díaz-Rubio and Santos Mañes ()
Additional contact information
Emilia Mira: Centro Nacional de Biotecnología/CSIC
Lorena Carmona-Rodríguez: Centro Nacional de Biotecnología/CSIC
Beatriz Pérez-Villamil: Univ. Complutense de Madrid, CIBERONC
Josefina Casas: Institute of Advanced Chemistry of Catalonia (IQAC-CSIC)
María Jesús Fernández-Aceñero: Univ. Complutense de Madrid, CIBERONC
Diego Martínez-Rey: Centro Nacional de Biotecnología/CSIC
Paula Martín-González: Centro Nacional de Biotecnología/CSIC
Ignacio Heras-Murillo: Centro Nacional de Biotecnología/CSIC
Mateo Paz-Cabezas: Univ. Complutense de Madrid, CIBERONC
Manuel Tardáguila: Centro Nacional de Biotecnología/CSIC
Tim D. Oury: University of Pittsburgh
Silvia Martín-Puig: Centro Nacional de Investigaciones Cardiovasculares
Rosa Ana Lacalle: Centro Nacional de Biotecnología/CSIC
Gemma Fabriás: Institute of Advanced Chemistry of Catalonia (IQAC-CSIC)
Eduardo Díaz-Rubio: Univ. Complutense de Madrid, CIBERONC
Santos Mañes: Centro Nacional de Biotecnología/CSIC

Nature Communications, 2018, vol. 9, issue 1, 1-18

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03079-1

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