Abstract
The incidence of prostate carcinoma is very low in Eastern countries, such as Japan, suggesting that life style conditions may play a crucial role in the development of this pathology. Dietary ω‐6 polyunsaturated fatty acids, such as linoleic (LA) and arachidonic (AA) acids, have been shown to stimulate the proliferation of prostate cancer cells after being converted into 5‐HETE by means of the 5‐lipoxygenase (5‐LOX) pathway. Blockade of 5‐LOX activity has been proposed as an attractive target for the prevention of the mitogenic action of dietary fats on prostate cancer. The 5‐LOX gene has been shown to carry a response element for the orphan nuclear receptor RORα (for its RORα1 isoform in particular) in its promoter region. We attempt to clarify whether activation of RORα might modulate the expression of 5‐LOX, thus interfering with the mitogenic activity of fatty acids in prostate cancer cells. We show that in androgen‐independent DU 145 prostate cancer cells, LA, AA and their metabolite 5‐HETE exert a strong stimulatory action on cell proliferation. This effect is completely counteracted by the simultaneous treatment of the cells with a non redox inhibitor of 5‐LOX activity. We then demonstrate that: i) RORα, and specifically its RORα1 isoform, is expressed in DU 145 cells; ii) activation of RORα, by means of the thiazolidinedione derivative CGP 52608 (the synthetic RORα activator), significantly reduces 5‐LOX expression, both at mRNA (as evaluated by comparative RT‐PCR) and at protein (as investigated by Western blot analysis) level (this was confirmed by the reduced activity of 5‐LOX in CGP 52608 treated cells); and iii) the treatment of DU 145 cells with CGP 52608 completely abrogated the proliferative action of both LA and AA. These results have been confirmed in another androgen‐independent prostate cancer cell line (PC3). Our data indicate that, by decreasing the expression of 5‐LOX, activation of RORα might interfere with the mitogenic activity of fatty acids on prostate cancer. We have shown previously that CGP 52608 reduces the proliferation and the metastatic behavior of DU 145 cells. These observations indicate that the orphan nuclear receptor RORα might be considered as a molecular target for the development of new chemopreventive or chemotherapeutic strategies for prostate carcinoma. © 2004 Wiley‐Liss, Inc.