Luteinizing hormone-releasing hormone agonist limits DU-145 prostate cancer growth by attenuating epidermal growth factor receptor signaling.

Advanced prostate cancer is treated initially by central suppression of androgen production by luteinizing hormone-releasing hormone (LHRH) agonists. Intriguingly, even hormone-independent cancers often show some, if only slight, growth retardation when these agonists are delivered in pharmacological doses. Previous studies have shown in cell lines and animal xenograft models that activation of peripheral LHRH receptors on prostate carcinoma cells lead to growth suppression. In parallel, there is a decrease of epidermal growth factor receptors (EGFRs) and activity. Because autocrine EGFR stimulation exists in most, if not all, prostate carcinomas and is required for cell proliferation, we asked whether LHRH signaling cross-attenuated EGFR to limit tumor growth. One possible mechanism was suggested by LHRH receptors triggering phospholipase-C (PLC) to activate protein kinase C (PKC) because PKC activation limits EGFR tyrosine kinase activity by phosphorylating EGFR at threonine 654. To determine the role of this cross-attenuation mechanism, we mutated the threonine 654 amino acid to an alanine (A654) to abrogate this inhibition. DU-145 cells stably expressing wild-type and A654 EGFR were grown as xenografts in the s.c. space of athymic mice. DU-145 cells, overexpressing wild-type EGFR, formed tumors in athymic mice that were inhibitable by goserelin acetate (Zoladex). Tumors expressing the A654 EGFR were resistant to this growth inhibition. These results paralleled in vitro studies in which goserelin acetate blocked proliferation of the WT DU-145 but not A654 DU-145 cells. These data support the model of LHRH agonists preventing EGFR-mediated tumor growth through a PKC pathway. This suggests new targets of modulatory intervention to limit the growth of androgen-independent prostate carcinomas.