Inhibition of MEK induces fas expression and apoptosis in lymphomas overexpressing Ras.
Published results implicate PI3 kinase as a target of oncogenic Ras activity leading to the suppression of Fas but whether other Ras targets (e.g. Raf-1) are also involved is unclear. Here we report that thymic lymphomas overexpressing Ras and Raf-1 exhibit low expression of Fas. We show that expression of Fas in these lymphomas can be increased not only in the presence of a specific inhibitor (LY294002) of P13 kinase, but also in the presence of specific inhibitor (PD98059) of MEK, downstream target of Raf-1. Both treatments result in accumulation of ERK in cytosol of lymphoma cells suggesting cross-talk between these two pathways regulating Fas expression. Treatment with PD98059 also results in apoptosis of the lymphoma cells but not of normal thymocytes expressing low Raf-1 levels. These observations provide evidence for involvement of Raf-1/MEK/ERK pathway in Ras-mediated inhibition of Fas expression and in selective promotion of survival of lymphoma cells.
Kalas
Wojciech
W
Polish Academy of Sciences, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw.
Kisielow
Pawel
P
Strzadala
Leon
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D008223:Lymphoma / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015398:Signal Transduction; D013953:Thymus Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D018631:ras Proteins / Q000235:genetics / Q000502:physiology*
D002867:Chromones; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019014:fas Receptor; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one