| First Author | Mira E | Year | 2018 |
| Journal | Nat Commun | Volume | 9 |
| Issue | 1 | Pages | 575 |
| PubMed ID | 29422508 | Mgi Jnum | J:338799 |
| Mgi Id | MGI:6119051 | Doi | 10.1038/s41467-018-03079-1 |
| Citation | Mira E, et al. (2018) SOD3 improves the tumor response to chemotherapy by stabilizing endothelial HIF-2alpha. Nat Commun 9(1):575 |
| abstractText | 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-2alpha (HIF-2alpha) stability and enhanced its binding to a specific VEC promoter region. EC-specific HIF-2alpha ablation prevented both the SOD3-mediated increase in VEC transcription and the enhanced Doxo effect. SOD3, VEC, and HIF-2alpha levels correlated positively in primary colorectal cancers, which suggests a similar interconnection of these proteins in human malignancy. |
