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Insulin-like Growth Factor-Binding Protein 3 Induces Caspase-Dependent Apoptosis Through a Death Receptor-Mediated Pathway in MCF-7 Human Breast Cancer Cells

Insulin-like Growth Factor-Binding Protein 3 Induces Caspase-Dependent Apoptosis Through a Death Receptor-Mediated Pathway in MCF-7 Human Breast Cancer Cells

Ho-Seong Kim, Angela R Ingermann, Junko Tsubaki, Stephen M Twigg, Gillian E Walker, Youngman Oh

Cancer Res. 2004 Mar 15;64(6):2229-37.

PMID: 15026367

Abstract:

Insulin-like growth factor-binding protein (IGFBP)-3 has been shown to potently inhibit cell proliferation in various cell systems. However, the specific mechanisms involved in the antiproliferative action of IGFBP-3 have yet to be elucidated. In the present study, we demonstrate that IGFBP-3 induces apoptosis in an insulin-like growth factor (IGF)-independent manner through the activation of caspases involved in a death receptor-mediated pathway in MCF-7 human breast cancer cells. Induction of IGFBP-3 using an ecdysone-inducible expression system inhibited DNA synthesis in an IGF-IGF receptor axis-independent fashion and resulted in the subsequent induction of apoptosis and an increase in caspase activity. Similar results were obtained when cells were transfected with GGG-IGFBP-3, an IGFBP-3 mutant unable to bind IGFs, corroborating the IGF-independent action of IGFBP-3. Additional caspase activity studies and immunoblot analyses using specific caspase substrates and/or caspase inhibitors revealed that the growth-inhibitory effect of IGFBP-3 results mainly from its induction of apoptosis (in particular, activation of caspase-8 and -7). Analyses of caspase-9 activity and release of cytochrome c into the cytosol confirmed that the mitochondria-mediated pathway is not involved. Taken together, these results show that IGFBP-3 expression leads to the induction of apoptosis through the activation of caspases involved in a death receptor-mediated pathway and that IGFBP-3 functions as a negative regulator of breast cancer cell growth, independent of the IGF-IGF receptor axis.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42413307	IGF-Binding Protein 7 human			Price

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