Contribution of phosphatidylinositol 3-kinase to radiation resistance in human melanoma cells

The activity of phosphatidylinositol 3-kinase (PI3K), a key component of mu ltiple signal transduction pathways, was investigated in early- and late-st age melanoma cells that have varying degrees of radiation resistance. Analy sis of PI3K biproducts (PI-3,4-P-2 and PI-3,4,5-triphosphate) revealed a di rect correlation between radiation resistance and levels of PI3K activity. Treating melanoma cells with wortmanin or LY294002, two different PI3K inhi bitors, decreased PI3K activity and caused a dose-dependent decrease in res istance to ultraviolet radiation. Lower resistance to radiation elicited by LY294002 coincided with increased apoptosis. To further establish the role of PI3K in radiation resistance, we transfected early-stage melanoma cells with the cDNA of p85, the regulatory subunit of PI3K. Clones that constitu tively overexpressed p85 exhibited a higher degree-of PI-3,4-P-2 synthesis and a corresponding increase in their resistance to ultraviolet radiation. The results of this study point to the role of PI3K and its biproducts in r adiation resistance of human melanoma cells. (C) 1999 Wiley-Liss, Inc.