Inositol pentakisphosphate promotes apoptosis through the PI 3-K/Akt pathway Journal Article
| Authors: | Piccolo, E.; Vignati, S.; Maffucci, T.; Innominato, P. F.; Riley, A. M.; Potter, B. V. L.; Pandolfi, P. P.; Broggini, M.; Iacobelli, S.; Innocenti, P.; Falasca, M. |
| Article Title: | Inositol pentakisphosphate promotes apoptosis through the PI 3-K/Akt pathway |
| Abstract: | Phosphoinositide 3-kinase (PI 3-K) is implicated in a wide array of biological and pathophysiological responses, including tumorigenesis, invasion and metastasis, therefore specific inhibitors of the kinase may prove useful in cancer therapy. We propose that specific inositol polyphosphates have the potential to antagonize the activation of PI 3-K pathways by competing with the binding of PtdIns(3,4,5)P3 to pleckstrin homology (PH) domains. Here we show that Ins(1,3,4,5,6)P5 inhibits the serine phosphorylation and the kinase activity of Akt/PKB. As a consequence of this inhibition, Ins(1,3,4,5,6)P5 induces apoptosis in ovarian, lung and breast cancer cells. Overexpression of constitutively active Akt protects SKBR-3 cells from Ins(1,3,4,5,6)P5-induced apoptosis. Furthermore, Ins(1,3,4,5,6)P5 enhances the proapoptotic effect of cisplatin and etoposide in ovarian and lung cancer cells, respectively. These results support a role for Ins(1,3,4,5,6)P5 as a specific inhibitor of the PI 3-K/ Akt signalling pathway, that may sensitize cancer cells to the action of commonly used anticancer drugs. |
| Keywords: | signal transduction; protein kinase b; controlled study; protein phosphorylation; oncoprotein; human cell; proto-oncogene proteins; drug activity; cisplatin; antineoplastic agents; antineoplastic agent; ovarian neoplasms; metabolism; gene overexpression; metastasis; apoptosis; ovary cancer; etoposide; lung neoplasms; lung cancer; enzyme activation; drug effect; pathology; tumor cells, cultured; enzyme activity; protein serine threonine kinase; phosphorylation; phosphatidylinositol 3 kinase; carcinogenesis; cancer invasion; lung tumor; cell culture; protein-serine-threonine kinases; ovary tumor; 1-phosphatidylinositol 3-kinase; chromones; morpholines; proto-oncogene proteins c-akt; sequence homology; 2 morpholino 8 phenylchromone; fibronectin; phosphoinositide 3-kinase; fibronectins; chromone derivative; inositol phosphate; morpholine derivative; akt1 protein, human; humans; human; female; priority journal; article; inositol polyphosphates; pleckstrin homology domain; protein kinase b-akt; inositol pentakisphosphate; inositol polyphosphate; 2-(4-morpholinyl)-8-phenyl-4h-1-benzopyran-4-one; inositol phosphates |
| Journal Title: | Oncogene |
| Volume: | 23 |
| Issue: | 9 |
| ISSN: | 0950-9232 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2004-03-04 |
| Start Page: | 1754 |
| End Page: | 1765 |
| Language: | English |
| DOI: | 10.1038/sj.onc.1207296 |
| PROVIDER: | scopus |
| PUBMED: | 14755253 |
| DOI/URL: | |
| Notes: | Oncogene -- Cited By (since 1996):63 -- Export Date: 16 June 2014 -- CODEN: ONCNE -- Source: Scopus |
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