Liver-derived IGF1 enhances the androgenic response in prostate

Abstract

Both IGF1 and androgens are major enhancers of prostate growth and are implicated in the development of prostate hyperplasia and cancer. The aim of the present study was to investigate whether liver-derived endocrine IGF1 modulates the androgenic response in prostate. Mice with adult, liverspecific inactivation of IGF1 (LI-IGF1 K/K mice) displayed an w80% reduction in serum IGF1 levels associated with decreased prostate weight compared with control mice (anterior prostate lobe K19%, P!0 . 05; dorsolateral prostate (DLP) lobe K35%, P!0 . 01; ventral prostate (VP) lobe K47%, P!0 . 01). Reduced androgen receptor (Ar) mRNA and protein levels were observed in the VP lobe (K34% and K30% respectively, both P!0 . 05 versus control mice). Analysis of prostate morphology showed reductions in both the glandular and fibromuscular compartments of the VP and DLP lobes that were proportional to the reductions in the weights of these lobes. Immunohistochemistry revealed reduced intracellular AR immunoreactivity in the VP and DLP lobes. The non-aromatizable androgen dihydrotestosterone increased VP weight to a lesser extent in orchidectomized (ORX) LI-IGF1 K/K mice than in ORX controls (K40%, P!0 . 05 versus control mice). In conclusion, deficiency of liver-derived IGF1 reduces both the glandular and fibromuscular compartments of the prostate, decreases AR expression in prostate, and reduces the stimulatory effect of androgens on VP weight. These findings may explain, at least in part, the well-known clinical association between serum IGF1 levels and conditions with abnormal prostate growth.

Nonalcoholic fatty liver disease is a negative risk factor for prostate cancer recurrence

“…An in vitro study showed that IGF1 promotes growth of primary prostate cell cultures and human prostate cancer cell lines (De Nunzio et al 2012). In other studies, transgenic mice overexpressing human IGF1 in basal epithelial cells of the prostate were reported to develop prostate carcinoma at a high rate (DiGiovanni et al 2000), and mice with global or liver-specific inactivation of IGF1 were associated with reduced prostate size and androgen-dependent prostate growth (Svensson et al 2008). In addition, a meta-analysis of 42 observational studies demonstrated that elevated circulating IGF1 levels were significantly associated with prostate cancer risk (odds ratio, 1.21; 95% CI, 1.07-1.36) (Rowlands et al 2009).…”

Androgens, diabetes and prostate cancer

“…In an LNCaP xenograft model, mice fed a high fat diet showed significantly increased serum insulin levels and experienced accelerated PCa growth compared to mice receiving a low fat diet, and serum from mice receiving the high fat diet was more mitogenic for LNCaP cells in vitro (Venkateswaran et al 2007). (DiGiovanni et al 2000), and mice with global or liver-specific inactivation of IGF1 show reduced prostate size and reduced androgen-dependent prostate growth (Svensson et al 2008). Indeed, a meta-analysis of 42 observational studies confirmed that raised circulating IGF1 levels were significantly associated with PCa risk (OR 1.21; 95% CI, 1.07-1.36), with weak evidence that this association was stronger for advanced PCa (Rowlands et al 2009).…”

An Androgen Receptor-MicroRNA-29a Regulatory Circuitry in Mouse Epididymis

“…As in the prostate (38), IGF1 enhanced AR expression and was directly suppressed by miR-29a in mouse epididymis. Therefore, the suppression of miR-29a by AR might be mediated or at least partially mediated by IGF1.…”

“…A previous study revealed that the AR protein level is decreased in prostate from Igf1 knock-out mice (38). Therefore, we determined whether IGF1 can also activate AR expression in mouse epididymal cells.…”