title: 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.
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D011905:Genes, ras; D051379:Mice; D009154:Mutation; D019700:Thrombospondin 1 / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D019700:Thrombospondin 1; D004318:Doxycycline