SOD3 improves the tumor response to chemotherapy by stabilizing endothelial HIF-2\u03b1

Emilia Mira,Mateo Paz-Cabezas,María Jesús Fernández-Aceñero,Manuel Tardáguila,Josefina Casas,Eduardo Díaz-Rubio,Gemma Fabriás,Silvia Martín-Puig,Santos Mañes,Rosa Ana Lacalle,Beatriz Pérez-Villamil,Lorena Carmona-Rodríguez,Ignacio Heras-Murillo,Tim D Oury,Paula Martín-González,Diego Martínez-Rey

doi:10.1038/s41467-018-03079-1

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.

Highlights

One drawback of chemotherapy is poor drug delivery to tumor cells, due in part to hyperpermeability of the tumor vasculature
SOD3−/− mice do not display any overt phenotype in basal conditions[22], and there were no major differences in endothelial cells (ECs) marker expression compared to WT mice (Supplementary Fig. 1)
Lov alone did not affect tumor growth kinetics, it increased the Doxo antitumor effect in WT (Fig. 1a) but not in SOD3−/− mice (Fig. 1b). This enhancement correlated with a two-fold increase in Doxo levels in Lovcompared to Vhcl-treated WT mouse tumors (Fig. 1c); Lov treatment had no effect on Doxo levels in tumors in SOD3−/− mice

Summary

Introduction

One drawback of chemotherapy is poor drug delivery to tumor cells, due in part to hyperpermeability of the tumor vasculature. 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 partial reduction of PHD2 levels does not increase vascular density in tumors but tightens EC adhesion by increasing VEC transcription, which improves vascular function and chemotherapeutic drug delivery[12,13]. These effects are associated with HIF-2α (but not HIF1α) stabilization in PHD2+/− haploinsufficient EC12; HIF-2α ( termed EPAS-1) but not HIF-1α induces VEC transcription[14]. HIF-2α effects on the tumor milieu appear to be cell type specific and dose dependent, suggesting that cancer therapy can be enhanced by selective, precise HIF-2α stabilization in endothelial but not in cancer cells

Methods

Results

Conclusion