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dc.contributor.authorMira, Emilia
dc.contributor.authorCarmona-Rodriguez, Lorena
dc.contributor.authorPerez-Villamil, Beatriz
dc.contributor.authorCasas, Josefina
dc.contributor.authorFernández-Aceñero, María Jesús
dc.contributor.authorMartinez-Rey, Diego
dc.contributor.authorMartin-Gonzalez, Paula
dc.contributor.authorHeras-Murillo, Ignacio 
dc.contributor.authorPaz-Cabezas, Mateo
dc.contributor.authorTardaguilal, Manuel
dc.contributor.authorOury, Tim D.
dc.contributor.authorMartin-Puig, Silvia 
dc.contributor.authorAna Lacalle, Rosa
dc.contributor.authorFabrias, Gemma
dc.contributor.authorDiaz-Rubio, Eduardo
dc.contributor.authorManes, Santos
dc.identifier.citationNat Commun. 2018; 9(1):575
dc.description.abstractOne drawback of chemotherapy is poor drug delivery to tumor cells, due in part to hyper-permeability 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-2 alpha (HIF-2 alpha) stability and enhanced its binding to a specific VEC promoter region. EC-specific HIF-2 alpha ablation prevented both the SOD3-mediated increase in VEC transcription and the enhanced Doxo effect. SOD3, VEC, and HIF-2 alpha levels correlated positively in primary colorectal cancers, which suggests a similar interconnection of these proteins in human malignancy.
dc.description.sponsorshipThe authors thank A Gonzalez-Martin for critical reading; L Iruela-Arispe, A Mantovani, Q Xu, L del Peso, and LM Redondo for reagents; MC Moreno and S Escudero for help with cell sorting; RM Peregil, N Rodriguez, N Dalmau, and JM Ballestero for technical assistance; and C Mark for editorial support. This work was funded by grants from the Spanish MINECO (SAF2014-54475-R, SAF2017-83732-R; AEI/FEDER, EU), the Comunidad de Madrid (B2017/BMD-3733; Inmunothercan-CM), and the Domingo-Martinez Foundation to S.M. S.M.-P. is supported by a Miguel Servet contract (CP09/00100), L.C.-R. is funded by the FPU program, and I.H.-M. and D.M.-R. were AECC summer fellowship recipients.
dc.publisherNature Publishing Group 
dc.titleSOD3 improves the tumor response to chemotherapy by stabilizing endothelial HIF-2 alpha
dc.typejournal article
dc.rights.licenseAtribución 4.0 Internacional*
dc.contributor.funderMinisterio de Economía y Competitividad (España) 
dc.contributor.funderComunidad de Madrid (España) 
dc.contributor.funderFundación Domingo Martínez 
dc.contributor.funderUnión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) 
dc.contributor.funderAsociación Española Contra el Cáncer 
dc.identifier.journalNature Communications
dc.repisalud.orgCNICCNIC::Grupos de investigación
dc.rights.accessRightsopen accesses_ES

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