A specific function for phosphatidylinositol 3-kinase α (p85α-p110α) in cell survival and for phosphatidylinositol 3-kinase β (p85α-p110β) in de novo DNA synthesis of human colon carcinoma cells

Abstract

We have previously shown an important function of phosphatidylinositol 3-kinase (P13K)α(p85α-p110α) and P13Kβ (p85-α-p110β) for DNA synthesis induced by various mitogens in non transformed fibroblasts and we now report a specific role of these enzymes in human colon cancer cell growth. Using antibodies specific to p110α and to p110β catalytic subunits, increase in P13Kα and P13Kβ activities was detected in 15/19 human tumour biopsies relative to adjacent normal mucosa of human colon and bladder. Increase in such activities was also observed in adenocarcinoma cell lines CaCo2, CO115, HCT 116, LS 174T and WiDr relative to non-transformed fibroblasts. Maximal P13Kα activity was observed for LS 174T and P13Kβ activity for WiDr cells. This was partly correlated with an increase in p110α and p110β protein levels both in some primary tumours and established cell lines, suggesting that P13K overexpression is involved in enzymatic deregulation. Functional consequence of such activation was assessed by a microinjection approach. An injection of neutralizing antibody specific to p110β in WiDr, HCT116 and CO 115 cells inhibited de novo DNA synthesis, whereas antibodies specific to p110γ had no effect. Neutralizing antibodies specific to p110α induced apoptosis, a response that was reverted by treating cells with the caspase inhibitor z-VAD-fmk. However anti-p110β and anti-p110γ antibodies did not affect cell survival. We concluded that P13Kα and P13Kβ play important roles in human colon cancer cell growth with a specific function for P13Kβ in de novo DNA synthesis and an involvement of P13Kα in cell survival.