Restoration of thrombospondin 1 expression in tumor cells harbouring mutant ras oncogene by treatment with low doses of doxycycline.

Abstract

Oncogenes act as inducers of tumor neovascularization, at least in part through suppression of endogenous angiogenesis inhibitors, e.g., thrombospondin 1 (TSP-1/THSP1). Therefore, restoration of TSP-1 levels can be viewed as a possible means to inhibit tumor angiogenesis. We observed that low concentrations (0.1-10 microg/ml) of doxycycline (but not those of related tetracycline) restore TSP-1 expression in H-ras oncogene-expressing tumor cell lines (528ras1, MT-Ras). Interestingly, this effect was relatively ras-specific, as doxycycline did not alter TSP-1 expression in several cell lines (e.g., 528neu2 fibrosarcoma, B16F1 melanoma, and Lewis lung carcinoma) harbouring other types of transforming alterations. Doxycycline-induced reversal of TSP down-regulation was abrogated under hypoxic conditions. Therefore, we conclude that, in vivo, TSP-1 is likely under dual and/or synergistic control of oncogenes and hypoxia-related pathways. Disruption of both components may be necessary for the 'rescue' of TSP-1 expression in ras-driven cancers.

• Authors: Wojciech Kalas, Sarah Gilpin, Joanne L Yu, Linda May, Halka Krchnakova, Paul Bornstein, Janusz Rak
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 310 Issue 1 Pg. 109-14 (Oct 10 2003) ISSN: 0006-291X [Print] United States
• PMID: 14511656 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Thrombospondin 1
• Doxycycline

Topics

• Animals
• Dose-Response Relationship, Drug
• Doxycycline (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Genes, ras
• Mice
• Mutation
• Thrombospondin 1 (metabolism)
• Tumor Cells, Cultured