Journal Article

2,3,7,8-Tetrachlorodibenzo-<i>p</i>-dioxin (TCDD) inhibits growth factor withdrawal-induced apoptosis in the human mammary epithelial cell line, MCF-10A

John W. Davis, Karla Melendez, Virginia M. Salas, Fredine T. Lauer and Scott W. Burchiel

in Carcinogenesis

Volume 21, issue 5, pages 881-886
Published in print May 2000 | ISSN: 0143-3334
Published online May 2000 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/21.5.881
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) inhibits growth factor withdrawal-induced apoptosis in the human mammary epithelial cell line, MCF-10A

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Previous studies have demonstrated that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases cell recovery in the human mammary epithelial cell line MCF-10A grown under growth factor-restricted conditions. TCDD was also found to mimic growth factor signaling pathways by stimulating the tyrosine phosphorylation of numerous effector molecules, and increased phosphatidylinositol 3-kinase (PI3K) activity in the absence of exogenously added growth factors. In the present studies, we have expanded on these initial results to show that TCDD (3–30 nM) increases cell recovery on days 2–6 by as much as 80% when insulin or epidermal growth factor (EGF) was removed from the media. The mechanism for this effect appears to be complex as TCDD inhibited apoptosis stimulated by EGF, or EGF and insulin, withdrawal by almost 80% as determined by Annexin V binding. However, withdrawal of insulin alone did not induce apoptosis even though TCDD did increase cell number in its absence. These results were corroborated by immunoblot analysis of poly(ADP-ribose) polymerase cleavage. Since TCDD stimulates PI3K activity, the phosphorylation status of Akt, a serine/threonine kinase that mediates PI3K-dependent inhibition of apoptosis, was examined. Immunoblot analysis revealed that TCDD causes a transient increase in the phosphorylated form of Akt that peaks at 6 h and disappears by 12 h. It appears that EGF stimulates an anti-apoptotic pathway, while insulin signals a pro-mitogenic pathway. By stimulating or mimicking one or both of these pathways TCDD may alter tightly regulated growth pathways in the MCF-10A cell line.

Keywords: AhR, aryl hydrocarbon receptor; DMSO, dimethyl sulfoxide; EGF, epidermal growth factor; IGF-I, insulin-like growth factor-I; IGF-IR, IGF-I receptor; PARP, poly(ADP-ribose) polymerase; PI, propidium iodide; PI3K, phosphatidylinsitol 3-kinase; PS, phosphatidylserine; SFH, EGF and insulin-deficient media; SFHE, insulin-deficient media; SFIH, EGF-deficient media; SFIHE, complete growth media; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Journal Article.  5285 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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