Most types of
prostate cancer (PCa) are usually initially responsive to androgenic regulation and, therefore, to
androgen ablation
therapy. However, in several patients
tumors may progress to
androgen resistance and be poorly responsive to any
therapy. Many factors may account for this progression to
androgen independence, including increased responsiveness to
estrogens and
peptide growth factors. The role of
estrogens in
androgen independence has been suggested by the observation that both primary and metastatic PCa express the
estrogen receptor (ER-beta), a recently discovered ER subtype. On the other hand,
peptide growth factors, like
IGF-1,
IGF-2, and the
insulin-like growth factor receptor (IGF-1R), may play a role in regulating growth, survival, and invasion of PCa cells. Here, we show that both
androgens and
estrogens markedly upregulate the IGF-1R expression in PCa cells by activating a nongenotropic pathway and sensitizing cells to the biological effects of
IGF-1. This effect is specific for IGF-1R because it does not involve the highly homologous
insulin receptor. IGF-1R upregulation is caused by increased
mRNA transcription. However, it does not require
steroid receptor binding to
DNA, but involves AR and ER binding to c-Src and subsequent activation of ERK1/2 and other cytoplasmatic
kinases, which eventually stimulate IGF-1R promoter activity. In conclusion, our data indicate that both
androgens and
estrogens contribute to IGF system deregulation in PCa and may play a role in
tumor progression to
androgen independence. Inhibition of the IGF-1R or the Src-ERK pathway should be considered, therefore, as an adjuvant
therapy in PCa.