ET-1 expression and growth inhibition of prostate cancer cells: a retinoid target with novel specificity.
Endothelin-1 (ET-1) is not only a potent vasoconstrictor but also serves as an important growth stimulator in various cancers, including breast, cervical, pancreatic, and prostate cancer. This suggests that blockage of ET-1 production may suppress tumor growth and possibly metastasis. We observed that certain synthetic retinoids, and all-trans-retinoic acid can repress LNCaP prostate cancer cell growth in vitro. In addition, these retinoid compounds counteracted exogenous ET-1-induced growth stimulation. Retinoid-dependent growth retardation of LNCaP cells coincided with suppression of ET-1 gene expression to a level undetectable by reverse transcription-PCR. Contrarily, the androgen-insensitive DU145 cells were refractory to retinoid treatment. To investigate the underlying mechanisms of the cell-specific response to retinoids, we transfected ET-1 promoter constructs containing wild-type or mutated AP-1 or GATA-2 site into prostate cancer cells. Distinct regulations of ET-1 promoter activity were found; in LNCaP cells, both binding sites are essential for optimal promoter activation, whereas in DU145 cells, additional promoter sequences and/or transcriptional factors seem to be involved. Furthermore, several anti-AP-1 selective retinoids failed to repress ET-1 promoter activity and to exhibit a cell growth-inhibitory effect on LNCaP cells, suggesting that different retinoid structural configurations are required for the inhibition of an AP-1 complex versus an AP-1/GATA-2 complex.
Hsu
J Y
JY
Sidney Kimmel Cancer Center, San Diego, California 92121, USA.
Pfahl
M
M
D004268:DNA-Binding Proteins / Q000502:physiology; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics; D050989:GATA2 Transcription Factor; D006801:Humans; D008297:Male; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D012176:Retinoids / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D019332:Endothelin-1; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; D012176:Retinoids; D018808:Transcription Factor AP-1; D014157:Transcription Factors