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      Insulin receptor compensates for IGF1R inhibition and directly induces mitogenic activity in prostate cancer cells


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          Hyperinsulinemia is a major complication associated with the development of insulin resistance. In addition to its normal spectrum of metabolic effects, insulin can act as a growth factor and has the ability to promote mitogenic activity. Thus, hyperinsulinemia is regarded as a potentially important cancer risk factor among diabetic patients. However, the mechanisms of action of insulin in the specific context of prostate cancer (PCa) and, in particular, the specific receptor that mediates its actions have not been elucidated yet. The aims of this study were to investigate whether insulin can directly induce mitogenic activities in PCa-derived cell lines and to examine the mechanisms responsible for these actions. To this end, we used several PCa-derived cell lines, representing early and advanced stages of the disease. Our results indicated that insulin induces cell proliferation in a dose-dependent fashion in the LNCaP, C4-2, and P69 cell lines. We also demonstrated that insulin enabled LNCaP and C4-2 cells to progress through the cell cycle. Immunoprecipitation assays revealed that insulin activated the insulin receptor (INSR), but not the IGF1 receptor (IGF1R). In addition, INSR was able to compensate for and mediate IGF1 mitogenic signals following IGF1R inhibition. In conclusion, insulin exhibits direct mitogenic activities in PCa cells, which are mediated exclusively through the INSR. Further research is needed to fully dissect the molecular mechanisms underlying the biological actions of insulin in PCa.

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          Insulin receptor isoforms and insulin receptor/insulin-like growth factor receptor hybrids in physiology and disease.

          In mammals, the insulin receptor (IR) gene has acquired an additional exon, exon 11. This exon may be skipped in a developmental and tissue-specific manner. The IR, therefore, occurs in two isoforms (exon 11 minus IR-A and exon 11 plus IR-B). The most relevant functional difference between these two isoforms is the high affinity of IR-A for IGF-II. IR-A is predominantly expressed during prenatal life. It enhances the effects of IGF-II during embryogenesis and fetal development. It is also significantly expressed in adult tissues, especially in the brain. Conversely, IR-B is predominantly expressed in adult, well-differentiated tissues, including the liver, where it enhances the metabolic effects of insulin. Dysregulation of IR splicing in insulin target tissues may occur in patients with insulin resistance; however, its role in type 2 diabetes is unclear. IR-A is often aberrantly expressed in cancer cells, thus increasing their responsiveness to IGF-II and to insulin and explaining the cancer-promoting effect of hyperinsulinemia observed in obese and type 2 diabetic patients. Aberrant IR-A expression may favor cancer resistance to both conventional and targeted therapies by a variety of mechanisms. Finally, IR isoforms form heterodimers, IR-A/IR-B, and hybrid IR/IGF-IR receptors (HR-A and HR-B). The functional characteristics of such hybrid receptors and their role in physiology, in diabetes, and in malignant cells are not yet fully understood. These receptors seem to enhance cell responsiveness to IGFs.
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            Establishment and characterization of a human prostatic carcinoma cell line (PC-3).

            The establishment, characterization, and tumorigenicity of a new epithelial cell line (PC-3) from a human prostatic adenocarcinoma metastatic to bone is reported. The cultured cells show anchorage-independent growth in both monolayers and in soft agar suspension and produce subcutaneous tumors in nude mice. Culture of the transplanted tumor yielded a human cell line with characteristics identical to those used initially to produce the tumor. PC-3 has a greatly reduced dependence upon serum for growth when compared to normal prostatic epithelial cells and does not respond to androgens, glucocorticoids, or epidermal or fibroblast gowth factors. Karyotypic analysis by quinacrine banding revealed the cells to be completely aneuploid with a modal chromosome number in the hypotriploid range. At least 10 distinctive marker chromosomes were identified. The overall karyotype as well as the marker chromosomes are distinct from those of the HeLa cell. Electron microscopic studies revealed many features common to neoplastic cells of epithelial origin including numerous microvilli, junctional complexes, abnormal nuclei and nucleoli, abnormal mitochondria, annulate lamellae, and lipoidal bodies. Overall, the functional and morphologic characteristics of PC-3 are those of a poorly-differentiated adenocarcinoma. These cells should be useful in investigating the biochemical changes in advanced prostatic cancer cells and in assessing their response to chemotherapeutic agents.
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              Prediagnostic body-mass index, plasma C-peptide concentration, and prostate cancer-specific mortality in men with prostate cancer: a long-term survival analysis.

              Excess body-mass index (BMI) has been associated with adverse outcomes in prostate cancer, and hyperinsulinaemia is a candidate mediator, but prospective data are sparse. We assessed the effect of prediagnostic BMI and plasma C-peptide concentration (reflecting insulin secretion) on prostate cancer-specific mortality after diagnosis. This study involved men diagnosed with prostate cancer during the 24 years of follow-up in the Physicians' Health Study. BMI measurements were available at baseline in 1982 and eight years later in 1990 for 2546 men who developed prostate cancer. Baseline C-peptide concentration was available in 827 men. We used Cox proportional hazards regression models controlling for age, smoking, time between BMI measurement and prostate cancer diagnosis, and competing causes of death to assess the risk of prostate cancer-specific mortality according to BMI and C-peptide concentration. Of the 2546 men diagnosed with prostate cancer during the follow-up period, 989 (38.8%) were overweight (BMI 25.0-29.9 kg/m(2)) and 87 (3.4%) were obese (BMI >/=30 kg/m(2)). 281 men (11%) died from prostate cancer during this follow-up period. Compared with men of a healthy weight (BMI <25 kg/m(2)) at baseline, overweight men and obese men had a significantly higher risk of prostate cancer mortality (proportional hazard ratio [HR] 1.47 [95% CI 1.16-1.88] for overweight men and 2.66 [1.62-4.39] for obese men; p(trend)<0.0001). The trend remained significant after controlling for clinical stage and Gleason grade and was stronger for prostate cancer diagnosed during the PSA screening era (1991-2007) compared with during the pre-PSA screening era (1982-1990) or when using BMI measurements obtained in 1990 compared with those obtained in 1982. Of the 827 men with data available for baseline C-peptide concentration, 117 (14%) died from prostate cancer. Men with C-peptide concentrations in the highest quartile (high) versus the lowest quartile (low) had a higher risk of prostate cancer mortality (HR 2.38 [95% CI 1.31-4.30]; p(trend)=0.008). Compared with men with a BMI less than 25 kg/m(2) and low C-peptide concentrations, those with a BMI of 25 kg/m(2) or more and high C-peptide concentrations had a four-times higher risk of mortality (4.12 [1.97-8.61]; p(interaction)=0.001) independent of clinical predictors. Excess bodyweight and a high plasma concentration of C-peptide both predispose men with a subsequent diagnosis of prostate cancer to an increased likelihood of dying of their disease. Patients with both factors have the worst outcome. Further studies are now needed to confirm these findings.

                Author and article information

                Endocr Connect
                Endocr Connect
                Endocrine Connections
                Bioscientifica Ltd (Bristol )
                28 February 2014
                01 March 2014
                : 3
                : 1
                : 24-35
                [1 ]Department of Human Molecular Genetics and Biochemistry Sackler School of Medicine, Tel Aviv University Tel Aviv, 69978Israel
                [2 ]Endocrinology and Diabetes Research Unit Schneider Children's Medical Center Petah Tikva, 49202Israel
                Author notes
                Correspondence should be addressed to H Werner Email: hwerner@ 123456post.tau.ac.il
                © 2014 The authors

                This work is licensed under a Creative Commons Attribution 3.0 Unported License

                : 10 December 2013
                : 7 January 2014

                insulin,insulin receptor,insulin-like growth factor-1 (igf1),igf1 receptor,prostate cancer


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