Endocrine Abstracts (2002) 3 P238

Interactions of vitamin D analogues with downstream effectors of insulin-like growth factor 1 (IGF-I) signalling

LC Lowe, C Mørk Hansen & KW Colston

Oncology, Gastroenterology Endocrinology and Metabolism, St Georges Hospital Medical School, London, UK.

Raised levels of IGF-I have been associated with risk of developing several cancers including breast carcinoma. In addition to promoting mitogenesis in breast cancer cells, a number of observations suggest a role for inhibition of apoptosis by IGF-I receptor activation. Ligand binding to IGF-IR leads to activation of both the phosphoinositide-3'-kinase (PI3K) and the Ras/Raf/MAPKinase pathways. Deprivation of serum growth factors induces apoptosis in MCF-7 breast cancer cells and this effect can be abrogated by supplementation of serum free medium (SFM) with IGF-I via activation of the PI3K pathway. Co-treatment of MCF-7 cells with the vitamin D analogue EB1089 can attenuate the anti-apoptotic actions of IGF-I. To investigate the mechanism(s) by which EB1089 prevents IGF-I-mediated cell survival we compared interactions between this analogue and IGF-I in parental MCF-7 cells and a stable subclone (MCF-7/VDR) that is resistant to the growth inhibitory and apoptosis inducing effects of vitamin D. IGF-I promoted survival of parental and MCF-7/VDR cells in SFM such that >90% viability was obtained with cultures incubated with 4nM IGF-I for 4 days. Co-treatment with 100nM EB1089 attenuated the effects of IGF-I in parental but not MCF-7/VDR cells. Attenuation of IGF-I effects in parental cells was accompanied by a decrease in IGF-I-mediated PI3K activation (as assessed by levels of phosphorylated Akt). Using phosphospecific antibodies we obtained evidence that EB1089 treatment of parental cells promotes the pro-apoptotic p38 MAPK but not the ERK/MAPK pathway. In addition MCF-7/VDR basally contain a higher proportion of phosphorylated to total Akt, compared with parental MCF-7 cells. This may in part account for their resistance to vitamin D analogues. However, both cell lines are sensitive to the PI3K inhibitor wortmannin suggesting that even in the presence of a higher proportion of phosphorylated Akt, MCF-7/VDR cell death can be induced by blocking this cell survival pathway.

This research is funded by The Breast Cancer Research Trust and the World Cancer Research Fund.

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