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Novel functional PI 3‐kinase antagonists inhibit cell growth and tumorigenicity in human cancer cell lines
Author(s) -
Razzini Giorgia,
Berrie Christopher P.,
Vignati Sara,
Broggini Massimo,
Mascetta Giuseppe,
Brancaccio Anna,
Falasca Marco
Publication year - 2000
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.14.9.1179
Subject(s) - inositol , phosphatidylinositol , protein kinase b , cancer cell , kinase , cell culture , cell growth , microbiology and biotechnology , pi3k/akt/mtor pathway , chemistry , biology , cancer , signal transduction , cancer research , biochemistry , receptor , genetics
ABSTRACT New efforts in cancer therapy are being focused at various levels of signaling pathways. With phosphoinositide 3‐kinase (PI3‐K) potentially being necessary for a range of cancer‐related functions, we have investigated the influence of selected inositol tristo hexakisphosphates on cell growth and tumorigenicity. We show that micromolar concentrations of inositol 1,3,4,5,6‐pentakisphosphate and inositol 1,4,5,6‐tetra‐kisphosphate [Ins(1,4,5,6)P 4 ] inhibit IGF‐1‐induced [ 3 H]‐thymidine incorporation in human breast cancer (MCF‐7) cells and the ability to grow in liquid medium and form colonies in agarose semisolid medium by small cell lung cancer (SCLC) cells, a human cancer cell line containing a constitutively active PI3‐K. In an ovarian cancer cell line that also contains a constitutively active PI3‐K (SKOV‐3 cells), Ins(1,4,5,6)P 4 again inhibited liquid medium growth. Furthermore, when applied extracellularly, inositol 1,3,4,5‐tetrakisphosphate was shown indeed to enter SCLC cells. These effects appeared specifically related to PH domains known to bind to phosphatidylinositol 3,4‐bisphosphate [PtdIns(3,4)P 2 ] and phosphatidylinositol 3,4,5‐trisphosphate [PtdIns(3,4,5)P 3 ], indicating involvement of the PI3‐K downstream target protein kinase B (PKB/Akt). This was further supported by inhibition of PKB/Akt PH domain membrane targeting in COS‐7 cells by Ins(1,4,5,6)P 4 . Thus, we propose that specific inositol polyphosphates inhibit PI3‐K by competing with PtdIns(3,4,5)P 3 ‐binding PH domains and that this occurs mainly at the level of the downstream PI3‐K target, PKB/Akt.—Razzini, G., Berrie, C. P., Vignati, S., Broggini, M., Mascetta, G., Brancaccio, A., Falasca, M. Novel functional PI 3‐kinase antagonists inhibit cell growth and tumorigenicity in human cancer cell lines. FASEB J. 14, 1179–1187 (2000)