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ET-1 Expression and Growth Inhibition of Prostate Cancer Cells: A Retinoid Target with Novel Specificity

Sidney Kimmel Cancer Center [J-Y. H., M. P.] and MAXIA Pharmaceuticals, Inc. [M. P.], San Diego, California

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.

¹ To whom requests for reprints should be addressed, at Sidney Kimmel Cancer Center, San Diego, CA 92121. Phone: (619) 623-9632; Fax: (619) 824-1967.

Received 6/29/98. Accepted 9/17/98.

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