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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.
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)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.
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.