Phosphatidylinositol 3-kinase (PI3-K) is a heterodimer of a regulatory subunit, p85, and a catalytic subunit, p110. A number of previous reports showed that PI3-K functions in diverse cellular phenomena such as cell proliferation, glucose catabolism, cell adhesion, and vesicle transport. It is also well known that a survival signal from the receptor tyrosine kinases utilizes Akt via PI3-K to protect cells from apoptosis. To examine the role of PI3-K in cellular sensitivity to genotoxic stresses such as cisplatin and ultraviolet (UV), we introduced deletion type p85 (Dp85) into two human glioblastoma cell lines (T98G and A172) and one melanoma cell line (G361). The Deltap85 works in a dominant-negative fashion on PI3-K activity by disrupting its p85 / p110 interaction. In all three transfected cell lines, the overexpression of Deltap85 rendered the cells markedly more sensitive to these DNA-damaging stresses than the cells transfected with the vector alone. Apoptosis was vigorously induced in cells overexpressing Dp85 following the treatment. The present results imply that PI3-K plays a critical role in determining cellular sensitivity to genotoxic stresses in human cancer cells, and that disruption of the p85 / p110 interaction of PI3-K may be a potential molecular target for developing a novel strategy for cancer treatment.