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Published on: July 21, 2018

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

G Razzini1, C P Berrie, S Vignati

  • 1Unit of Physiopathology of Cell Signalling, Department of Cell Biology and Oncology, Consorzio Mario Negri Sud, via Nazionale, 66030 Santa Maria Imbaro (Chieti), Italy.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|June 2, 2000
PubMed

Insights

Specific inositol polyphosphates, like inositol 1,4,5,6-tetrakisphosphate, inhibit cancer cell growth by targeting the phosphoinositide 3-kinase (PI3-K) pathway. This discovery offers new avenues for cancer therapy development.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Cancer therapies increasingly target specific signaling pathways.
  • Phosphoinositide 3-kinase (PI3-K) is crucial for cancer cell functions.
  • Inositol polyphosphates are investigated for their role in cellular signaling.

Purpose of the Study:

  • To investigate the influence of inositol tris- to hexakisphosphates on cancer cell growth and tumorigenicity.
  • To explore the potential of specific inositol polyphosphates as inhibitors of the PI3-K pathway.

Main Methods:

  • Treatment of human breast cancer (MCF-7) and small cell lung cancer (SCLC) cells with inositol polyphosphates.
  • Assay of IGF-1-induced thymidine incorporation.
  • Evaluation of cell growth in liquid medium and colony formation in soft agar.
  • Analysis of PH domain binding and membrane targeting of PKB/Akt.

Main Results:

  • Inositol 1,3,4,5,6-pentakisphosphate and inositol 1,4,5,6-tetrakisphosphate [Ins(1,4,5,6)P(4)] inhibited thymidine incorporation in MCF-7 cells.
  • Ins(1,4,5,6)P(4) inhibited growth and colony formation in SCLC cells and growth in SKOV-3 cells.
  • Extracellular inositol 1,3,4,5-tetrakisphosphate entered SCLC cells.
  • Ins(1,4,5,6)P(4) inhibited PKB/Akt PH domain membrane targeting, suggesting PI3-K pathway involvement.

Conclusions:

  • Specific inositol polyphosphates, particularly Ins(1,4,5,6)P(4), inhibit cancer cell proliferation and tumorigenicity.
  • These effects are mediated by competition with PtdIns(3,4,5)P(3)-binding PH domains, primarily affecting the PI3-K downstream target PKB/Akt.
  • This mechanism presents a novel therapeutic strategy targeting the PI3-K pathway in cancer.

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