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.
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References
Alessi DR, Andjelkovich M, Caudwell B, Cron P, Morrice N, Cohen P and Hemmings BA . (1996). EMBO J., 15, 6541–6551.
Aoudjit F and Vuori K . (2001). Oncogene, 20, 4995–5004.
Banfic H, Downes CP and Rittenhouse SE . (1998). J. Biol. Chem., 273, 11630–11637.
Baraud C, Henzel WJ and Baeuerle PA . (1999). Proc. Natl. Acad. Sci. USA, 96, 429–434.
Berrie CP and Falasca M . (2000). FASEB J., 14, 2618–2622.
Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Anderson MJ, Arden KC, Blenis J and Greenberg ME . (1999). Cell, 19, 857–868.
Burgering B and Coffer P . (1995). Nature, 376, 599–602.
Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S and Reed JC . (1998). Science, 282, 1318–1321.
Chang HW, Aoki M, Fruman D, Auger K, Bellacosa A, Tsichlis P, Cantley LC, Roberts T and Vogt P . (1997). Science, 276, 1848–1850.
Clark AS, West K, Streicher S and Dennis PA . (2002). Mol. Cancer Ther., 1, 707–717.
Corvera S and Czech MP . (1998). Trends Cell Biol., 8, 442–446.
Di Cristofano A, Pesce B, Cordon-Cardo C and Pandolfi PP . (1998). Nat. Genet., 19, 348–355.
Downward J . (1998). Curr. Opin. Cell Biol., 10, 262–267.
Duke RC and Cohen JJ . (1992). Current Protocols in Immunology, Coligan JE, et al. (eds). John Wiley & Sons: New York, pp. 3.17.1–3.7.16.
Falasca M, Logan SK, Lehto VP, Baccante G, Lemmon MA and Schlessinger J . (1998). EMBO J., 17, 414–422.
Franke TF, Kaplan DR and Cantley LC . (1997b). Cell, 88, 435–437.
Franke TF, Kaplan DR, Cantley LC and Toker A . (1997a). Science, 275, 665–668.
Frech M, Andjelkovich M, Ingley E, Reddy KK, Falck JR and Hemmings BA . (1997). J. Biol. Chem., 272, 8474–8481.
Fruman DA, Meyers RE and Cantley LC . (1998). Annu. Rev. Biochem., 67, 481–507.
Gottesman MM . (2002). Annu. Rev. Med., 53, 615–627.
Haslam RJ, Koide HB and Hemmings BA . (1993). Nature, 363, 309–310.
Kane LP, Shapiro VS, Stokoe D and Weiss A . (1999). Curr. Biol., 9, 601–604.
Kavran JM, Klein DE, Lee A, Falasca M, Isakoff SJ, Skolnik EY and Lemmon MA . (1998). J. Biol. Chem., 273, 30497–30508.
Kennedy S, Wagner A, Conzen S, Jordan J, Bellacosa A, Tsichlis P and Hay N . (1997). Genes Dev., 11, 701–713.
Khwaja A, Rodriguez-Viciana P, Wennstrom S, Warne PH and Downward J . (1997). EMBO J., 16, 2783–2793.
Klippel A, Kavanaugh WM, Pot D and Williams LT . (1997). Mol. Cell. Biol., 17, 338–344.
Leevers SJ, Vanhaesebroeck B and Waterfield MD . (1999). Curr. Opin. Cell Biol., 11, 219–225.
Lemmon MA and Ferguson KM . (1998). Curr. Top. Microbiol. Immunol., 228, 39–74.
Lemmon MA and Ferguson KM . (2000). Biochem. J., 350, 1–18.
Lemmon MA, Falasca M, Ferguson KM and Schlessinger J . (1997). Trends Cell Biol., 7, 237–242.
Maehama T and Dixon JE . (1998). J. Biol. Chem., 273, 13375–13378.
Maffucci T and Falasca M . (2001). FEBS Lett., 506, 173–179.
Mills SJ, Riley AM, Mahon MF and Potter BVL . (2003). Chem. Eur. J., 9, 6207–6214.
Moore SM, Rintoul RC, Walker TR, Chilvers ER, Haslett C and Sethi T . (1998). Cancer Res., 58, 5239–5247.
Mosmann T . (1983). J. Immunol. Methods, 65, 55–63.
Ng SS, Tsao MS, Nicklee T and Hedley DW . (2001). Clin. Cancer Res., 7, 3269–3275.
Rameh LE and Cantley LC . (1999). J. Biol. Chem., 274, 8347–8350.
Razzini G, Berrie CP, Vignati S, Broggini M, Mascetta G, Brancaccio A and Falasca M . (2000). FASEB J., 14, 1179–1187.
Riley AM, Guédat P, Schlewer G, Spiess B and Potter BVL . (1998). J. Org. Chem., 63, 295–305.
Rintoul R and Sethi T . (2002). Clin. Sci., 102, 417–424.
Sethi T, Rintoul RC, Moore SM, MacKinnon AC, Salter D, Choo C, Chilvers ER, Dransfield I, Donnelly SC, Strieter R and Haslett C . (1999). Nat. Med., 5, 662–668.
Shamsuddin AM . (1999). Anticancer Res., 19, 3733–3766.
Shaw G . (1996). BioEssays, 18, 35–46.
Shayesteh L, Lu Y, Kuo WL, Baldocchi R, Godfrey T, Collins C, Pinkel D, Powell B, Mills GB and Gray JW . (1999). Nat. Genet., 21, 99–102.
Shears SB . (2001). Cell Signal, 13, 151–158.
Stein RC . (2001). Endocr. Relat. Cancer, 8, 237–248.
Stokoe D, Stephens LR, Copeland T, Gaffney PR, Reese CB, Painter GF, Holmes AB, McCormick F and Hawkins PT . (1997). Science, 277, 567–570.
Szwergold BS, Grahamm RA and Brown TR . (1987). Biochem. Biophys. Res. Commun., 149, 874–881.
Takeuchi H, Kanematsu T, Misumi Y, Sakane F, Konishi H, Kikkawa U, Watanabe Y, Katan M and Hirata M . (1997). Biochim. Biophys. Acta, 1359, 275–285.
Thomas CC, Deak M, Alessi DR and van Aalten DM . (2002). Curr. Biol., 12, 1256–1262.
Vanhaesebroeck B, Leevers SJ, Panayotou G and Waterfield MD . (1997). Trends Biochem. Sci., 22, 267–272.
Vikhanskaya F and Broggini M . (2002). Int. Rev. Cytol., 219, 157–198.
Vincent SP, Lehn JM, Lazarte J and Nicolau C . (2002). Bioorg. Med. Chem., 10, 2825–2834.
Wang X, Gorospe M, Huang Y and Holbrook NJ . (1997). Oncogene, 15, 2991–2997.
Acknowledgements
We thank Professor MA Horton for support, Dr A Saiardi for critical reading of the manuscript, Drs SJ Mills and C Liu for gifts of some synthetic compounds and Dr MJ Quon for pCis2-Myr-Akt. This work was supported by a grant from Compagnia di San Paolo (Programma Oncologia) and from the Italian Health Ministry (02/171) to MB and by a Wellcome Trust Programme Grant (060554) to BVLP. MF is supported by an endowment from the Dr Mortimer and Mrs Theresa Sackler Trust.
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Piccolo, E., Vignati, S., Maffucci, T. et al. Inositol pentakisphosphate promotes apoptosis through the PI 3-K/Akt pathway. Oncogene 23, 1754–1765 (2004). https://doi.org/10.1038/sj.onc.1207296
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DOI: https://doi.org/10.1038/sj.onc.1207296
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