Cis-retinol dehydrogenase: 9-cis-retinol metabolism and its effect on proliferation of human MCF7 breast cancer cells.
9-Cis-retinoic acid (RA) suppresses cancer cell proliferation via binding and activation of nuclear receptors, retinoid X receptors (RXRs). In vivo, 9-cis-RA is formed through oxidation of 9-cis-retinol by cis-retinol dehydrogenase (cRDH), an enzyme that we characterized previously. Since 9-cis-RA is a potent inhibitor of breast cancer cell proliferation, we hypothesized that overexpression of cRDH in breast cancer cells would result in increased production of 9-cis-RA, which in turn would suppress cell proliferation. To investigate this hypothesis, MCF7 human breast carcinoma cells were transduced with cRDH cDNA (LRDHSN/MCF7), and the growth kinetics and retinoid profiles of cells were examined following treatment with 9-cis-retinol. LRDHSN/MCF7 cells showed a marked reduction in cell numbers (60-80%) upon treatment with 9-cis-retinol compared to vehicle alone. Within 24 h of treatment, approximately 75% of the 9-cis-retinol was taken up and metabolized by LRDHSN/MCF7 cells. Despite the rapid uptake and oxidation of 9-cis-retinol to 9-cis-retinal, 9-cis-RA was not formed in these cells. We detect at least one novel metabolite formed from both 9-cis-retinol and 9-cis-retinal that may play a role in inhibition of MCF7 cell proliferation. Our studies demonstrate that 9-cis-retinol in combination with cRDH inhibits breast cancer cell proliferation by production of retinol metabolites other than RA.
Paik
Jisun
J
Department of Pathobiology, University of Washington, Seattle, WA 98195, United States.
Blaner
William S
WS
Swisshelm
Karen
K
D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D049109:Cell Proliferation / Q000187:drug effects*; D004224:Diterpenes; D005260:Female; D006801:Humans; D012172:Retinaldehyde / Q000737:chemistry / Q000494:pharmacology*; D047488:Retinoid X Receptors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004224:Diterpenes; D047488:Retinoid X Receptors; C031390:9-cis-retinal; D000429:Alcohol Oxidoreductases; C105846:retinol dehydrogenase 5; D012172:Retinaldehyde