Estrogen metabolism in human colorectal cancer cells.
Epidemiological and "in vitro" studies support a direct role of estrogens in the pathogenesis and/or progression of colorectal cancer (CRC). Recent observations suggest a local synthesis of 17beta-estradiol (E(2)). In the present study, the CRC estrogen receptor beta (ERbeta) positive HCT8, HCT116, DLD-1 and LoVo cell lines were evaluated for expression of functional 17beta-hydroxysteroid dehydrogenase (17betaHSD) types 1, 2, 3, and 4. RT-PCR analysis revealed that while 17betaHSD1 and 17betaHSD4 were expressed in all the four cell lines, 17betaHSD2 and 17betaHSD3 were expressed in a cell-specific manner. The interconversion of tritiated estrone (E(1)) or E(2) evaluated by thin layer chromatography of conditioned media revealed that in HCT8, HCT116, and DLD-1 cells both reductive and oxidative activities were present, the latter showing K(m) values (approximately 10 microM) 40-fold higher than the former (approximately 250 nM). On the contrary, in LoVo cells, estrogens were almost (approximately 90%) completely metabolized to hydrophile compounds. Charcoal-dextrane (DC) stripped fetal calf serum (FCS) (10%), E(2) (10nM), Vitamin D(3) (100nM) and the combined E(2) and Vitamin D(3) treatment were evaluated for modulation of 17betaHSD isoenzymes gene expression and activity. Gene expression and activity of 17betaHSD reductive and oxidative isoenzymes were respectively inhibited and enhanced by Vitamin D(3) in HCT8 and LoVo cells. Surprisingly, DC-FCS induced a marked increase of estrogen metabolism toward hydrophile metabolites in all four cell lines. In conclusion, our results clearly show that metabolism of estrogens by 17betaHSD isoenzymes is functional and modulated by external stimuli in continuous neoplastic colonic epithelial cell lines.
Fiorelli
G
G
Department of Clinical Physiopathology, University of Florence, Florence, Italy.
Picariello
L
L
Martineti
V
V
Tognarini
I
I
Tonelli
F
F
Brandi
M L
ML
D002455:Cell Division; D015179:Colorectal Neoplasms / Q000378:metabolism*; D004958:Estradiol / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D010641:Phenotype; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D004967:Estrogens; D004958:Estradiol