The antiapoptotic effect of fibroblast growth factor-2 is mediated through nuclear factor-kappaB activation induced via interaction between Akt and IkappaB kinase-beta in breast cancer cells.
Fibroblast growth factor-2 (FGF-2) is known for its mitogenic and motogenic effects on breast cancer cells. Here, we demonstrate that FGF-2 is also a potent stimulator of breast cancer cell survival, as it counteracts the apoptotic activity of the C2 ceramide analogue and various chemotherapeutic agents (5-fluorouracil, camptothecin, etoposide) in ... MCF-7, T47-D and BT-20 cells. The use of pharmacological inhibitors (PD98059, wortmannin, LY294002, SN50) and transfection with negative dominants (IkappaBm, p110(PI3K (phosphoinositide 3-kinase))*DeltaK, AktND) or small interfering RNA targeted against Akt indicated that PI3K/Akt and nuclear factor-kappaB (NF-kappaB), but not p42/p44 MAP-kinases, were required to stimulate FGF-2 antiapoptotic activity. The activation of NF-kappaB was dependent on PI3K/Akt, and using a combination of approaches based on immunoprecipitation, Western blotting and proteomics (two-dimensional electrophoresis and mass spectrometry), we identified the beta form of IkappaB kinase (IKKbeta) as a target of Akt signaling. The selective disruption of IKKbeta using small interfering RNA induced a potent inhibition of Akt-mediated activation of NF-kappaB and cell survival, indicating the functional involvement of IKKbeta in FGF-2 antiapoptotic signaling. Together, these results demonstrate Akt/IKKbeta interaction in NF-kappaB pathways, thereby emphasizing the potential of these proteins as therapeutic targets in breast cancer.
Mesh Terms:
Apoptosis, Blotting, Western, Breast Neoplasms, Cell Line, Tumor, Electrophoresis, Gel, Two-Dimensional, Enzyme Activation, Female, Fibroblast Growth Factor 2, Humans, I-kappa B Kinase, Immunoprecipitation, Mass Spectrometry, NF-kappa B, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Transfection
Apoptosis, Blotting, Western, Breast Neoplasms, Cell Line, Tumor, Electrophoresis, Gel, Two-Dimensional, Enzyme Activation, Female, Fibroblast Growth Factor 2, Humans, I-kappa B Kinase, Immunoprecipitation, Mass Spectrometry, NF-kappa B, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Transfection
Oncogene
Date: Aug. 18, 2005
PubMed ID: 15856005
View in: Pubmed Google Scholar
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