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Fibroblast growth factor and insulin-like growth factor differentially modulate the apoptosis and G1 arrest induced by anti-epidermal growth factor receptor monoclonal antibody

Oncogene volume 20, pages 1913–1922 (2001)Cite this article

Abstract

DiFi human colon carcinoma cells are stimulated by the transforming growth factor-α (TGF-α)/epidermal growth factor (EGF) receptor autocrine loop. Exposure of DiFi cells to monoclonal antibody (mAb) 225, which blocks ligand-induced activation of the EGF receptor, induces G1 arrest and subsequent cell death via apoptosis. We investigated the signal pathways by which basic fibroblast growth factor (bFGF) and insulin-like growth factor-1 (IGF-1) modulate mAb 225-induced G1 arrest and apoptosis in DiFi cells. Both bFGF and IGF-1 activated the mitogen-activated protein kinase (MAPK) kinase (MEK) pathway in DiFi cells. Additionally, IGF-1 activated the phosphoinositide 3-kinase (PI-3K)/Akt pathway. Both bFGF and IGF-1 inhibited mAb 225-induced apoptosis; however, bFGF provided sustained protection against apoptosis, while the protection by IGF-1 was only temporary. Also, bFGF reversed the mAb 225-induced increase in the p27Kip1 level, inhibition of cyclin-dependent kinase-2 (CDK-2) activity, dephosphorylation of the retinoblastoma (Rb) protein and the resultant G1 arrest of the cells. In contrast, IGF-1 did not reverse such effects by mAb 225. The prevention of mAb 225-induced G1 arrest and apoptosis in DiFi cells by bFGF was sensitive to the MEK/MAPK inhibitor PD98059 but not to the PI-3K inhibitor LY294002. In contrast, inhibition of apoptosis by IGF-1 in DiFi cells was sensitive only to LY294002 and not to PD98059. These results further our understanding of how mAb 225 induces apoptosis in DiFi cells.

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Abbreviations

EGF:

epidermal growth factor

TGF-α:

transforming growth factor-α

bFGF:

basic fibroblast growth factor

IGF-1:

insulin-like growth factor-1

mAb:

monoclonal antibody

MAPK:

mitogen-activated protein kinase

MEK:

MAPK kinase

PI-3K:

phosphoinositide 3-kinase

CDK:

cyclin-dependent kinase

Caspase:

cysteinyl aspartate-specific proteinase

ELISA:

enzyme-linked immunosorbent assay.

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Acknowledgements

The authors are grateful to Mr Michael Worley of the Department of Scientific Publications for editorial assistance with the manuscript. This study was supported in part by a Start-up fund to Z Fan by The University of Texas MD Anderson Cancer Center, and by a Bristol-Myers Squibb Research Award to J Mendelsohn.

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Authors and Affiliations

  1. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Texas, 77030, Houston, TX, USA

    Bolin Liu, Min Fang, Yang Lu, John Mendelsohn & Zhen Fan

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  1. Bolin Liu
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  2. Min Fang
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Correspondence to Zhen Fan.

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Liu, B., Fang, M., Lu, Y. et al. Fibroblast growth factor and insulin-like growth factor differentially modulate the apoptosis and G1 arrest induced by anti-epidermal growth factor receptor monoclonal antibody. Oncogene 20, 1913–1922 (2001). https://doi.org/10.1038/sj.onc.1204277

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