A specific function for phosphatidylinositol 3-kinase alpha (p85alpha-p110alpha) in cell survival and for phosphatidylinositol 3-kinase beta (p85alpha-p110beta) in de novo DNA synthesis of human colon carcinoma cells.
We have previously shown an important function of phosphatidylinositol 3-kinase (PI3K)alpha(p85alpha-p110alpha) and PI3Kbeta (p85-alpha-p110beta) 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 p110alpha and to p110beta catalytic subunits, increase in PI3Kalpha and PI3Kbeta 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 PI3Kalpha activity was observed for LS 174T and PI3Kbeta activity for WiDr cells. This was partly correlated with an increase in p110alpha and p110beta protein levels both in some primary tumours and established cell lines, suggesting that PI3K overexpression is involved in enzymatic deregulation. Functional consequence of such activation was assessed by a microinjection approach. An injection of neutralizing antibody specific to p110beta in WiDr, HCT116 and CO 115 cells inhibited de novo DNA synthesis, whereas antibodies specific to p110gamma had no effect. Neutralizing antibodies specific to p110alpha induced apoptosis, a response that was reverted by treating cells with the caspase inhibitor z-VAD-fmk. However anti-p110beta and anti-p110gamma antibodies did not affect cell survival. We concluded that PI3Kalpha and PI3Kbeta play important roles in human colon cancer cell growth with a specific function for PI3Kbeta in de novo DNA synthesis and an involvement of PI3Kalpha in cell survival.
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CNRS UPR-1086 CRBM, 1919 Route de Mende, 34293 Montpellier Cedex 05, France.
Chapuis
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Roche
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D016475:3T3 Cells / Q000201:enzymology; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002295:Carcinoma, Transitional Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004273:DNA, Neoplasm / Q000096:biosynthesis*; D004789:Enzyme Activation; D006801:Humans; D007527:Isoenzymes / Q000502:physiology; D051379:Mice; D008845:Microinjections; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D004273:DNA, Neoplasm; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases