Targets of 17beta-oestradiol-induced apoptosis in colon cancer cells: a mechanism for the protective effects of hormone replacement therapy?
Epidemiological studies show a strong link between postmenopausal hormone replacement therapy and decreased incidence of colorectal cancer. The colon cancer cell line, COLO 205, develops sensitivity to 17beta-oestradiol (E(2)) in apoptosis assays with increasing passage number (>40), and we hypothesised that genes selectively regulated in multiply passaged cells were likely to be important in E(2)-related apoptosis. Gene array analysis was used to compare the patterns of genes up- or down-regulated in E(2)-sensitive and -insensitive cells. For some genes, changes in mRNA expression were confirmed by protein expression analyses. Changes found in response to E(2) in multiply passaged cells, but not minimally passaged cells, included induction of growth arrest and DNA damage-inducible protein 153 (GADD153), and repression of Kirsten-Ras 2B (K-Ras-2B), metastasis inhibition factor NM23 and vascular endothelial growth factor. A second group of genes was regulated with E(2) exposure in both cell types, and is unlikely to be critically involved in E(2)-associated apoptosis. These included up-regulation of butyrate response factor 1 (BRF1) and down-regulation of c-jun and the breast cancer associated ring domain gene known as BARD1. By comparing control arrays from the two cell populations, cAMP-response element-binding protein (CBP), which is associated with steroid receptor-dependent target gene transcription and the oncoprotein, tyrosine kinase-T3 (TRK-T3), were up-regulated whereas retinoic acid receptor alpha (RARalpha) was down-regulated in multiply passaged cells. This study provides evidence for selective regulation of genes in colon cancer cells by E(2), indicates which of those regulated are likely to be involved in induced apoptosis, and suggests genes likely to be responsible for facilitation.
Qiu
Yan
Y
Division of Medical Sciences, The Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Langman
Michael J S
MJ
Eggo
Margaret C
MC
D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000473:pathology*; D053938:DNA Fragmentation; D004958:Estradiol / Q000494:pharmacology*; D015914:Estrogen Replacement Therapy; D015870:Gene Expression; D019073:HT29 Cells; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D042461:Vascular Endothelial Growth Factor A; D004958:Estradiol