Abstract
Aims/HypothesisIn different cancers types, insulin receptor isoform composition or insulin receptor substrate (IRS) isoforms are different to healthy tissue. This may be a molecular link to increased cancer risk in diabetes and obesity. Since this is yet unclear for prostate cancer, we investigated IR isoform composition and IRS balance in prostate cancer compared to benign and tumor adjacent benign prostate tissue and brought this into relation to cell proliferation.MethodsWe studied 23 benign prostate samples from radical cystectomy or benign prostatic hyperplasia surgery, 30 samples from benign tissue directly adjacent to prostate cancer foci and 35 cancer samples from different patients. RNA expression levels for insulin receptor isoforms A and B, IRS-1, IRS-2, and IGF-1 receptor were assessed by quantitative real-time RT-PCR. In addition, RNA- and protein expression of the cell cycle regulator p27Kip1 was quantified by real-time RT-PCR and immunohistochemistry.ResultsInsulin receptor isoform A to B ratio was significantly higher in cancer as well as in tumor adjacent benign prostate tissue compared to purely benign prostates (p<0.05). IRS-1 to IRS-2 ratios were lower in malignant than in benign prostatic tissue (p<0.05). These altered ratios both in cancer and adjacent tissue were significantly associated with reduced p27Kip1 content (p<0.02). Interestingly, IGF-1 receptor levels were significantly lower in patients with type 2 diabetes (p = 0.0019).Conclusions/InterpretationWe found significant differences in the insulin signaling cascade between benign prostate tissue and prostate cancer. Histological benign tissue adjacent to cancer showed expression patterns similar to the malignancies. Our findings suggest a role of the insulin signaling pathway in prostate cancer and surrounding tissue and can hence be relevant for both novel diagnostic and therapeutic approaches in this malignancy.
Highlights
Type 2 diabetes (T2DM) is associated with increased risk for several cancer types [1,2,3]
insulin receptor substrate (IRS)-1 to IRS-2 ratio was altered with relatively higher IRS-2 expression (Figure 1 B)
While there were no differences between groups in the insulin receptor (IR) isoform A to insulin-like growth factor (IGF)-1 receptor ratio (Figure 1 C), IR isoform B to IGF-1 receptor ratio was significantly lower in cancer and adjacent tissue compared to benign prostate (Figure 1 D)
Summary
Type 2 diabetes (T2DM) is associated with increased risk for several cancer types [1,2,3]. The risk for the most prevalent cancer in men, prostate cancer, seems to be unaltered by diabetes [4] but this is thought to be due to lower testosterone levels in T2DM [3,5,6]. For many types of cancer, alterations in the insulin signaling cascade have been reported. This starts at the level of the insulin receptor (IR). While overexpression of IR in prostate cancer and higher activity of the signaling chain downstream has been reported [9,10,11], isoform configuration in this cancer has not been studied yet
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