Journal
ONCOGENE
Volume 28, Issue 2, Pages 289-296Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2008.382
Keywords
ubiquitin; degradation; hypoxia
Funding
- Australian National Health and Medical Research Council (NHMRC) [400321, 509331]
- NATIONAL CANCER INSTITUTE [R01CA111515] Funding Source: NIH RePORTER
Ask authors/readers for more resources
Tumor hypoxia induces the upregulation of hypoxiainducible factor 1 alpha (Hif-1 alpha), which in turn induces the expression of genes including VEGF to recruit new blood vessel outgrowth, enabling tumor growth and metastasis. Interference with the Hif-1 pathway and neoangiogenesis is an attractive antitumor target. The hydroxylation of Hif-1 alpha by prolyl-hydroxylase (PHD) proteins during normoxia serves as a recognition motif for its proteasomal degradation. However, under hypoxic conditions, hydroxylation is inhibited and furthermore, PHD proteins are themselves polyubiquitylated and degraded by Siah ubiquitin ligases. Our data demonstrate for the first time that inhibition of the interaction between Siah and PHD proteins using a fragment derived from a Drosophila protein ( phyllopod) interferes with the PHD degradation. Furthermore, cells stably expressing the phyllopod fragment display reduced upregulation of Hif-1 alpha protein levels and Hif-1-mediated gene expression under hypoxia. In a syngeneic mouse model of breast cancer, the phyllopod fragment reduced tumor growth and neoangiogenesis and prolonged survival of the mice. In addition, levels of Hif-1 alpha and its target Glut-1 are reduced in tumors expressing the phyllopod fragment. These data show, in a proof-of-principle study, that Siah protein, the most upstream component of the hypoxia pathway yet identified, is a viable drug target for antitumor therapies.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available