Inositol pentakisphosphate promotes apoptosis through the PI 3-K/Akt pathway.
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.
Piccolo
Enza
E
Department of Medicine, The Sackler Institute, University College London, 5, University Street, London WC1E 6JJ, UK.
Vignati
Sara
S
Maffucci
Tania
T
Innominato
Pasquale F
PF
Riley
Andrew M
AM
Potter
Barry V L
BV
Pandolfi
Pier Paolo
PP
Broggini
Massimo
M
Iacobelli
Stefano
S
Innocenti
Paolo
P
Falasca
Marco
M
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
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