Expression of prolyl-hydroxylase-1 (PHD1/EGLN2) suppresses hypoxia inducible factor-1alpha activation and inhibits tumor growth.
Hypoxic stress is one of the major selective pressures in the microenvironment of solid tumors, and overcoming this restriction is essential for tumor progression. One of the key factors driving the cellular response to lack of oxygen is hypoxia inducible factor (HIF), a key transcriptional factor. The level of the alpha subunit of HIF-1 is regulated by rapid degradation that is controlled by a family of prolyl hydroxylases (PHDs/EGLNs), the activity of which depends on oxygen availability. Our study shows that ectopic expression of mPHD1 suppressed accumulation of HIF-1alpha and secretion of Vascular Endothelial Growth Factor after treatment of cells with a hypoxia-mimetic drug. Furthermore, when colon carcinoma cells expressing mPHD1 were injected into nude mice, tumor growth was inhibited, and the inhibition of tumor growth was correlated with increased necrosis and a striking decrease in microvessel density. These data demonstrate that inhibition of hypoxia-induced activation of HIF-1alpha through activation of HIF-hydroxylase can provide a novel therapeutic strategy for inhibition of tumor growth and neovascularization and support the development of gene transfer approaches based on the activation of HIF-prolyl hydroxylases.
Erez
Neta
N
Departments of Molecular Cell Biology and. Experimental Animals, The Weizmann Institute of Science, Rehovot, Israel. varda.rotter@weizmann.ac.il
Milyavsky
Michael
M
Eilam
Raya
R
Shats
Igor
I
Goldfinger
Naomi
N
Rotter
Varda
V
D000818:Animals; D002455:Cell Division / Q000502:physiology; D015687:Cell Hypoxia; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D003676:Deferoxamine / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D011393:Procollagen-Proline Dioxygenase / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000502:physiology; D015533:Transcriptional Activation / Q000502:physiology; D014183:Transplantation, Heterologous
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C085984:PHD1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D011393:Procollagen-Proline Dioxygenase; D003676:Deferoxamine