2024-03-28T12:05:56Zhttp://repisalud.isciii.es/oai/requestoai:repisalud.isciii.es:20.500.12105/66882023-08-31T06:52:43Zcom_20.500.12105_2145com_20.500.12105_2051com_20.500.12105_2144col_20.500.12105_2146
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
2041-1723
http://hdl.handle.net/20.500.12105/6688
29422508
10.1038/s41467-018-03079-1
Nature Communications
SOD3 improves the tumor response to chemotherapy by stabilizing endothelial HIF-2 alpha