2026-07-23T18:45:33Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/66882024-09-27T09:25:11Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Mira, Emilia author Carmona-Rodriguez, Lorena author Perez-Villamil, Beatriz author Casas, Josefina author Fernández-Aceñero, María Jesús author Martinez-Rey, Diego author Martin-Gonzalez, Paula author Heras-Murillo, Ignacio author Paz-Cabezas, Mateo author Tardaguilal, Manuel author Oury, Tim D. author Martin-Puig, Silvia author Ana Lacalle, Rosa author Fabrias, Gemma author Diaz-Rubio, Eduardo author Manes, Santos author 2018 One 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. Nat Commun. 2018; 9(1):575 10.1038/s41467-018-03079-1 2041-1723 Nature Communications 29422508 http://hdl.handle.net/20.500.12105/6688 SOD3 improves the tumor response to chemotherapy by stabilizing endothelial HIF-2 alpha