Insulin-like growth factors (IGFs) promote growth and survival of many types of tumor cells. Epidemiologic studies have implicated carcinogenesis with high levels of IGFs in circulation or in tissues. The levels of IGF binding proteins (IGFBPs) have been associated with reduced risk for prostate and other cancers. Experimental studies have implicated high levels of IGF-I directly and IGFBP-3 inversely in prostate cancer growth, survival, and progression. However, recent evidence suggests a much weaker association of IGF-I with prostate cancer development and a stronger antagonistic association of IGFBP-3 with prostate cancer progression. Considering the clonal heterogeneity and unpredictable progression pattern of prostate cancer, the role of any single growth factor or its regulator (IGFBP) as a single determining factor is limited. This review is a critical appraisal of the role of IGFs, IGFBP, and IGF-I receptor (the IGF axis) in both experimental and clinical prostate cancer genesis and progression.
"The insulin-like growth factor (IGF) axis, which consists of two ligands (IGF-I and IGF-II) that principally signal via the type 1 IGF receptor (IGF-IR) and a family of six high-affinity IGF-binding proteins (IGFBPs), has an important role in cancer (Pollak, 2008). Research has clearly established that the IGF axis has a very important role in the development and progression of many epithelial cancers, including prostate (Meinbach and Lokeshwar, 2006). At the cellular level the IGF-I receptor appears to have a fundamental role in maintaining the transformed phenotype for many cancer cells (Baserga et al, 2003). "
[Show abstract][Hide abstract] ABSTRACT: The development of androgen independence, chemo-, and radioresistance are critical markers of prostate cancer progression and the predominant reasons for its high mortality. Understanding the resistance to therapy could aid the development of more effective treatments.
The aim of this study is to investigate the effects of insulin-like growth factor-binding protein-2 (IGFBP-2) on prostate cancer cell proliferation and its effects on the response to docetaxel.
DU145 and PC3 cells were treated with IGFBP-2, insulin-like growth factor I (IGF-I) alone or in combination with blockade of the IGF-I receptor or integrin receptors. Cells were also treated with IGFBP-2 short interfering ribonucleic acid with or without a PTEN (phosphatase and tensin homologue deleted on chromosome 10) inhibitor or docetaxel. Tritiated thymidine incorporation was used to measure cell proliferation and Trypan blue cell counting for cell death. Levels of IGFBP-2 mRNA were measured using RT-PCR. Abundance and phosphorylation of proteins were assessed using western immunoblotting.
The IGFBP-2 promoted cell growth in both cell lines but with PC3 cells this was in an IGF-dependent manner, whereas with DU145 cells the effect was independent of IGF receptor activation. This IGF-independent effect of IGFBP-2 was mediated by interaction with β-1-containing integrins and a consequent increase in PTEN phosphorylation. We also determined that silencing IGFBP-2 in both cell lines increased the sensitivity of the cells to docetaxel.
The IGFBP-2 has a key role in the growth of prostate cancer cells, and silencing IGFBP-2 expression reduced the resistance of these cells to docetaxel. Targeting IGFBP-2 may increase the efficacy of docetaxel.
British Journal of Cancer 05/2011; 104(10):1587-93. DOI:10.1038/bjc.2011.127 · 4.84 Impact Factor
"It is important to note in this study that in pups exposed to test diets from conception, the combination of high Se with high isoflavones resulted in the lowest weight gain (Figure 1A), the lowest serum leptin (Figure 3A), and the lowest serum IGF-1 concentrations (Figure 4A) of all four dietary treatments. This finding has obvious implications for men in whom prostate cancer risk is increased by higher fat mass , higher serum leptin [5-7,73], and/or higher IGF-1 levels [3,4,74,75]. "
[Show abstract][Hide abstract] ABSTRACT: High dietary intake of selenium or isoflavones reduces risk factors for prostate cancer. We tested whether combined supplementation of these two dietary components would reduce prostate cancer risk factors in rats more than supplementation of each component individually.
Male Noble rat pups were exposed from conception to diets containing an adequate (0.33-0.45 mg/kg diet) or high (3.33-3.45 mg/kg) concentration of selenium as Se-methylselenocysteine and a low (10 mg/kg) or high (600 mg/kg) level of isoflavones in a 2 x 2 factorial design. Pups consumed their respective diets until sacrifice at 35, 100, or 200 days. Male Noble rat breeders, whose exposure to the diets began after puberty, were sacrificed at 336 days. Rats were weighed biweekly. Blood was collected at the time of sacrifice and body fat and prostates were dissected and weighed. Serum levels of leptin, IGF-1, and testosterone were determined using ELISA kits. Serum levels of isoflavones were assayed by GC/MS. Liver activity of selenium-dependent glutathione peroxidase 1 was measured as an indicator of selenium status.
Serum isoflavone concentrations were nearly 100-fold higher at 35 days of age (1187.1 vs. 14.4 ng/mL, mean +/- SD) in pups fed the high vs. low isoflavone diets, and remained so at 100 and 200 days, and in breeders. There were no dietary differences in liver glutathione peroxidase activity in pups or breeders. High isoflavone intake significantly (p = 0.001-0.047) reduced body weight in rat pups from 35 days onward, but not in breeders. Body fat and leptin were likewise significantly reduced by high isoflavones in pups while effects in breeders were less pronounced but still significant. High intake of Se and isoflavones each decreased serum IGF-1 in pups at 100 and 200 days, but not in breeders. No consistent dietary effects were observed on serum testosterone or relative weights of prostates. In pups, the combination of high isoflavones and high selenium produced the lowest weight gain, the lowest serum leptin, and the lowest serum IGF-1 concentrations of all four diets.
Combined intake of high selenium and high isoflavones may achieve greater chemopreventive effects than either compound individually. The timing of supplementation may determine the significance of its effects.
"However, the role of IGF1 in adult animals is difficult to evaluate in these mice strains due to the possible effect of the absence of IGF1 activity during development. Moreover, there is a local production of IGF1 in the prostate (Kaplan et al. 1999, Meinbach & Lokeshwar 2006), which is depleted in mice with global IGF1 knockout. By contrast, the LI-IGF1 K/K mice do not have decreased liver IGF1 expression until the inactivation Figure 1 Effects of liver-derived IGF1 on prostate morphology and androgen receptor (AR) immunoreactivity. "
[Show abstract][Hide abstract] 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, liver-specific inactivation of IGF1 (LI-IGF1(-/-) mice) displayed an approximately 80% reduction in serum IGF1 levels associated with decreased prostate weight compared with control mice (anterior prostate lobe -19%, P<0.05; dorsolateral prostate (DLP) lobe -35%, P<0.01; ventral prostate (VP) lobe -47%, P<0.01). Reduced androgen receptor (Ar) mRNA and protein levels were observed in the VP lobe (-34% and -30% 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(-/-) mice than in ORX controls (-40%, 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.
Journal of Endocrinology 10/2008; 199(3):489-97. DOI:10.1677/JOE-08-0406 · 3.72 Impact Factor
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