Glucocorticoids (GC) enhance p21 expression and induce G1 phase cell cycle arrest in MCF-7 cells –the possible role of GC receptors and their co-regulator Free

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Glucocorticoids (GC) are commonly co-administered with anti-cancer drugs to prevent drug-induced allergic reaction or nausea/vomiting. GC receptors (GCR) are ubiquitous in cancer cells and GCR have been linked to signal transduction pathways pertinent to cell growth and apoptosis. We have previously reported that GC affect growth and/or chemosensitivity of common human cancers. This study examines the effect of the GC on the growth in a human breast cancer cell line, MCF-7, which contains relative high level of GCR (6.4x10⁴/cell). We found that dexamethasone (DEX), at clinically achievable concentration (0.01-1.0μM) inhibits cell growth of MCF-7 cells while induces no cellular apoptosis. The effects of DEX on cell cycle phases and cell cycle regulators were examined by Western blot and flow cytometry study. The results showed that DEX induced p21 up-regulation and caused G1 phase arrest of MCF-7. Addition of excess amounts of a structure homologue of DEX, RU486, completely abolished the growth suppression effect of DEX, suggesting that DEX act via GCR-related signal transduction pathways. Furthers, DEX has no effect on the growth of MCF-7/GCR(-), an MCF-7 subclone contains vary low levels of GCR (<1x10³/cell). The expression of 27 steroid receptor co-regulators was examined by RT-PCR. Compared with MCF-7, MCF-7/GCR(-) contains no detectable level of CBP300, HDAC1, and significantly lower levels of NCOR1, TIF2, GCN5L2, and ARA70. Transfection of human GCR restored the expression of GCR and all these co-regulators and sensitivity to DEX in MCF-7/GCR(-) cells. We conclude that GC enhance p21 expression and thereby inhibit the growth of MCF-7 cells via GCR dependent pathway; and GCR affect the expression of several steroid receptor co-regulators. The importance of GCR-mediated regulation of their co-regulators in DEX-induced growth inhibition of MCF-7 cells needs to be further investigation. (This work was partially supported by grants from the National Science Council (NSC 92-2314-B-002-105), the Ministry of Education (89-B-FA01-1-4), Taiwan, R.O.C.)