Flowchart: Preparation: IGf-1r
 

 


Text Box: IGF-1                  

                                      

                                                 

Breast cancer

Colorectal Carcinomas                                              

Text Box: IGF-1rLongevity

 

 

          

 

                                             

Text Box: Akt Text Box: ER
Text Box: Insuline Text Box: Vegf
 


                                                                    

                           

   2007/8-1/33                                                         

Ann Surg Oncol. 2007 Jul 26; [Epub ahead of print] Links

Targeting of Insulin-like Growth Factor-I Receptor with a Monoclonal Antibody Inhibits Growth of Hepatic Metastases from Human Colon Carcinoma in Mice.

Bauer TW, Fan F, Liu W, Camp ER, Yang A, Somcio RJ, Bucana CD, Singh R, Ellis LM.

Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.

BACKGROUND: Colorectal carcinomas (CRC) express high levels of insulin-like growth factor-I/II (IGF-I/II) and the receptor (IGF-IR). We hypothesized that selective inhibition of IGF-IR would inhibit hepatic growth of human CRC in mice. METHODS: Human CRC cells were treated in vitro with anti-IGF-IR monoclonal antibody (MoAB) with and without oxaliplatin to assess cytotoxicity. The effect of anti-IGF-IR MoAB on IGF-I-induced vascular endothelial growth factor (VEGF) production in human CRC cells was assessed by Northern blot and ELISA. We injected human CRC cells intrahepatically in nude mice, and then administered anti-IGF-IR MoAB with and without oxaliplatin. We delayed treatment in one group until large hepatic tumors were present. We assessed tumors for apoptosis, proliferation, and angiogenesis. RESULTS: Anti-IGF-IR MoAB and oxaliplatin inhibited CRC cell growth in vitro and combination treatment was even more effective. IGF-I stimulation of CRC cells resulted in significant upregulation of VEGF and this was completely inhibited by pretreatment with anti-IGF-IR MoAB. Anti-IGF-IR MoAB significantly inhibited hepatic growth of tumors in mice. Anti-IGF-IR MoAB plus oxaliplatin led to a significantly greater inhibition of tumor growth. Anti-IGF-IR MoAB plus oxaliplatin was just as effective at inhibiting growth of larger, more advanced liver tumors. Anti-IGF-IR MoAB, alone and in combination with oxaliplatin, led to a significant increase in tumor cell apoptosis, and a significant inhibition of tumor cell proliferation and angiogenesis. CONCLUSIONS: These findings suggest that IGF-IR is a potential target for therapy in patients with advanced CRC.

PMID: 17653802 [PubMed - as supplied by publisher]

Diabetologia. 2007 Dec;50(12):2534-2543. Epub 2007 Sep 18.Click here to read Links

IGF-1 receptor signalling determines the mitogenic potency of insulin analogues in human smooth muscle cells and fibroblasts.

Eckardt K, May C, Koenen M, Eckel J.

Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Auf’m Hennekamp 65, D-40225, Dusseldorf, Germany, eckel@uni-duesseldorf.de.

AIMS/HYPOTHESIS: Mitogenic activity of insulin and insulin analogues and the involvement of the IGF-1 receptor (IGF-1R) is still a controversial issue. We compared levels of the proteins IGF-1R and insulin receptor (InsR) in fibroblasts and smooth muscle cells from healthy donors and assessed the downstream signalling and growth-promoting activity of insulin and insulin analogues. METHODS: DNA synthesis was monitored in human fibroblasts and coronary artery smooth muscle cells. Using small interfering RNAs, the levels of IGF-1 and InsR were reduced by 95 and 75%, respectively. RESULTS: Enhanced mitogenic potency of insulin and insulin analogues was observed which correlated with increased levels of IGF-1R and/or IRS-1. A reduction in the IGF-1R level significantly blunted stimulation of Akt phosphorylation by IGF-1, AspB10 and glargine by 72, 58 and 40%, respectively. Akt phosphorylation in response to insulin remained unaffected. Silencing of InsR did not significantly alter Akt phosphorylation in response to IGF-1, AspB10 and glargine. IGF-1R knockdown reduced the stimulation of DNA synthesis in response to IGF-1 and glargine to a level identical to that produced by insulin. CONCLUSIONS/INTERPRETATION: These data show a prominent role of IGF-1R/Akt signalling in mediating the mitogenic effects of insulin analogues. Regular insulin stimulates DNA synthesis by exclusively activating InsR, whereas insulin analogues mainly signal through IGF-1R. It is suggested that inter-individual differences in the levels of proteins of the IGF-1R system may function as a critical determinant of the mitogenic potency of insulin analogues.

PMID: 17898992 [PubMed - as supplied by publisher]

Breast Cancer Res Treat. 2006 Oct;99(3):275-88. Epub 2006 Jun 5.Click here to read Links

The relationship between the insulin-like growth factor-1 system and the oestrogen metabolising enzymes in breast cancer tissue and its adjacent non-cancerous tissue.

Chong YM, Colston K, Jiang WG, Sharma AK, Mokbel K.

Department of Cellular & Molecular Medicine, St George's Hospital, London, UK. kelvin.ymchong@gmail.com

AIMS: Previous studies have shown that oestrogen and Insulin-like Growth Factor-1 (IGF-1) act synergistically and cross-stimulatory while the oestrogen receptor (ER) and IGF-1R downstream signalling pathways interact at many levels. We investigate the relationship between the ER, and IGF-1R and their ligands in a series of human breast cancer tissue and adjacent non-cancerous tissue (ANCT). METHODS: A series of 139 pairs of breast cancer tissue and ANCT were obtained and divided into ER positive and ER negative groups based on tumour ER alpha immunostaining. All samples were processed for real-time quantitative-PCR to measure IGF-1, IGF-1R, ER alpha, STS and Cyp-19 mRNA levels. In addition, ER positive MCF-7 and ER negative MDA-MB-231 cell lines were treated separately with IGF-1 and an IGF-1R inhibitor called Tyrphostin AG1024 to see the effects of stimulating and inhibiting the IGF-1R. MCF-7 cell line was also treated with 4-hydroxytamoxifen. The mRNA levels of IGF-1, IGF-1R, ER alpha, STS and Cyp-19 of treated cell lines were measured and compared to those of non-treated controls. Data generated was normalised to Cytokeratin-19 mRNA levels. RESULTS: IGF-1R expression was higher in tumour tissue compared to ANCT (P = 0.038) while IGF-1 expression was marginally higher in ANCT compared to tumour tissue only in the ER positive samples (P = 0.098). ER positive tumours had a higher expression of IGF-1 compared to ER negative tumours (P = 0.001) while IGF-1R, STS and Cyp-19 expression were higher in ER negative tumours (P = 0.000, 0.000 and 0.006 respectively). There was no difference in STS or Cyp-19 expression in tumours or ANCT. Using Spearman's Correlation test, IGF-1 positively correlated with STS, Cyp-19 and ER alpha in ER positive and negative groups (Coefficient = +0.497, +0.662 and +0.651 respectively, P = 0.000 in all). IGF-1R correlated with IGF-1, STS, Cyp-19 and ER alpha only in the ER negative tumours (Coefficient = +0.620, +0.394, +0.692 and +0.662 respectively, P = 0.000, 0.012, 0.000 and 0.000 respectively). In cell lines, IGF-1 treatment led to an increase in the mean expression of IGF-1, IGF-1R, STS and Cyp-19 in both cell lines while ER alpha expression increased only in MCF-7. IGF-1R inhibition caused a decrease in expression of all five genes in MDA-MB-231 but not in the MCF-7 cell line. Treatment with 4-hydroxytamoxifen caused a decrease in expression of all five genes. CONCLUSIONS: IGF-1R is over-expressed in malignant tissue. IGF-1 is expressed at higher levels in ER positive tumours probably as a result of oestrogen stimulation while IGF-1R expression is higher in ER negative samples as an adaptation to lower local IGF-1 levels. An IGF-1 paracrine relationship may exist between tumour and ANCT but for STS and Cyp-19, there may be an autocrine-paracrine relationship. The IGF-1 ligand-receptor system is an important regulator of oestrogen production while oestrogen may be involved in stimulating IGF-1 expression. The expression of oestrogen synthesising enzymes is higher in ER negative breast cancers which may be due to the lack of oestrogen negative feedback or contribution from the overexpression of IGF-1R.

PMID: 16752221 [PubMed - indexed for MEDLINE]

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Breast Cancer Res Treat. 2006 Oct;99(3):323-31. Epub 2006 Jun 5. Links

An association between a common variant (G972R) in the IRS-1 gene and sex hormone levels in post-menopausal breast cancer survivors.

Fan J, McKean-Cowdin R, Bernstein L, Stanczyk FZ, Li AX, Ballard-Barbash R, McTiernan A, Baumgartner R, Gilliland F.

Integrated Substance Abuse Programs, Neuropsychiatric Institute, University of California, 1640 S. Sepulveda Boulevard, Suite 200, Los Angeles, CA 90025, USA.

Insulin receptor substrate-1 (IRS-1) is a key downstream signaling molecule common to both the insulin and IGF signaling pathways that can interact with the estrogen pathway to regulate breast cell growth. We investigated whether a putative functional variant for IRS-1 (G972R) influences circulating levels of sex hormones, sex hormone binding globulin (SHBG), C-peptide, and insulin-like growth factor 1 (IGF-1) levels among post-menopausal African-American and non-Hispanic white breast cancer patients enrolled in the Health, Eating, Activity, and Lifestyle (HEAL) Study. Circulating levels of sex hormones and growth factors can influence breast cancer recurrence and survival. Serum estrone, estradiol, testosterone, SHBG, IGF-1 and C-peptide were measured in 468 patients at 30+ months post diagnosis. Non-protein bound hormone levels (free estradiol, free testosterone) were calculated. In African-American patients, the IRS-1 variant was associated with increased serum levels of estrone (p = 0.02), free estradiol (p = 0.04), total testosterone (p = 0.04), free testosterone (p = 0.006) and decreased levels of sex hormone-binding globulin (p = 0.02). No association was present for white patients. Our findings provide suggestive evidence that IRS-1 G972R variant may be associated with circulating levels of sex hormones and SHBG in African American breast cancer survivors.

PMID: 16752222 [PubMed - indexed for MEDLINE]

IGF-1 protects cardiac myocytes from hyperosmotic stress-induced apoptosis via CREB.

Maldonado C, Cea P, Adasme T, Collao A, Diaz-Araya G, Chiong M, Lavandero S.

Departamento de Bioquimica y Biologia Molecular, Facultad de Ciencias Quimicas y Farmaceuticas, Universidad de Chile, Santiago, Chile; Centro FONDAP Estudios Moleculares de la Celula, Universidad de Chile, Santiago, Chile.

Hyperosmotic stress stimulates a rapid and pronounced apoptosis in cardiac myocytes which is attenuated by insulin-like growth factor-1 (IGF-1). Because in these cells IGF-1 induces intracellular Ca(2+) increase, we assessed whether the cyclic AMP response element-binding protein (CREB) is activated by IGF-1 through Ca(2+)-dependent signalling pathways. In cultured cardiac myocytes, IGF-1 induced phosphorylation (6.5+/-1.0-fold at 5min), nuclear translocation (30min post-stimulus) and DNA binding activity of CREB. IGF-1-induced CREB phosphorylation was mediated by MEK1/ERK, PI3-K, p38-MAPK, as well as Ca(2+)/calmodulin kinase and calcineurin. Exposure of cardiac myocytes to hyperosmotic stress (sorbitol 600mOsm) decreased IGF-1-induced CREB activation Moreover, overexpression of a dominant negative CREB abolished the anti-apoptotic effects of IGF-1. Our results suggest that IGF-1 activates CREB through a complex signalling pathway, and this transcription factor plays an important role in the anti-apoptotic action of IGF-1 in cultured cardiac myocytes.

PMID: 16168389 [PubMed - as supplied by publisher]

J Lab Clin Med. 2006 May;147(5):234-41.

Related Articles, Links

 
Coordinate activation of intracellular signaling pathways by insulin-like growth factor-1 and platelet-derived growth factor in rat hepatic stellate cells.

Bridle KR, Li L, O'neill R, Britton RS, Bacon BR.

Division of Gastroenterology and Hepatology, Saint Louis University Liver Center, Saint Louis University School of Medicine, St. Louis, Missouri.

Proliferation of activated hepatic stellate cells (HSC) is an important event in the development of hepatic fibrosis. Insulin-like growth factor-1 (IGF-1) has been shown to be mitogenic for HSC, but the intracellular signaling pathways involved have not been fully characterized. Thus, the aims of the current study were to examine the roles of the extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3-K) and p70-S6 kinase (p70-S6-K) signaling pathways in IGF-1- and platelet-derived growth factor (PDGF)-induced mitogenic signaling of HSC and to examine the potential crosstalk between these pathways. Both IGF-1 and PDGF increased ERK, PI3-K and p70-S6-K activity. When evaluating potential crosstalk between these signaling pathways, we observed that PI3-K is required for p70-S6-K activation by IGF-1 and PDGF, and is partially responsible for PDGF-induced ERK activation. PDGF and IGF-1 also increased the levels of cyclin D1 and phospho-glycogen synthase kinase-3beta. Coordinate activation of ERK, PI3-K and p70-S6-K is important for perpetuating the activated state of HSC during fibrogenesis.

PMID: 16697771 [PubMed - in process]