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.
authors.affiliation: Department of Medicine, The Sackler Institute, University College London, 5, University Street, London WC1E 6JJ, UK.
authors.forename: Enza
authors.initials: E
authors.lastname: Piccolo
authors.forename: Sara
authors.initials: S
authors.lastname: Vignati
authors.forename: Tania
authors.initials: T
authors.lastname: Maffucci
authors.forename: Pasquale F
authors.initials: PF
authors.lastname: Innominato
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Riley
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: Massimo
authors.initials: M
authors.lastname: Broggini
authors.forename: Stefano
authors.initials: S
authors.lastname: Iacobelli
authors.forename: Paolo
authors.initials: P
authors.lastname: Innocenti
authors.forename: Marco
authors.initials: M
authors.lastname: Falasca
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D007295:Inositol Phosphates / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D009025:Morpholines / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D002867:Chromones; D002945:Cisplatin; D005353:Fibronectins; D007295:Inositol Phosphates; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C013571:inositol pentaphosphate; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human