Novel functional PI 3-kinase antagonists inhibit cell growth and tumorigenicity in human cancer cell lines

Giorgia Razzini, Christopher P. Berrie, Sara Vignati, Massimo Broggini, Giuseppe Mascetta, Anna Brancaccio, Marco Falasca

Research output: Contribution to journalArticlepeer-review

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 tris-to 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-tetrakisphosphate [Ins(1,4,5,6)P4] inhibit IGF-1-induced [3H]-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)P4 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)P2] and phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3], 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)P4. Thus, we propose that specific inositol polyphosphates inhibit PI3-K by competing with PtdIns(3,4,5)P3-binding PH domains and that this occurs mainly at the level of the downstream PI3-K target, PKB/Akt.

Original languageEnglish
Pages (from-to)1179-1187
Number of pages9
JournalFASEB Journal
Volume14
Issue number9
Publication statusPublished - 2000

Keywords

  • Antitumor agents
  • Inositol polyphosphates
  • PH domain-binding antagonists
  • Phosphatidylinositols

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

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