Flowchart: Preparation: IGf-1
 

 


Text Box: Leptin                  

                                      

                                                  

Breast cancer

Colorectal Carcinomas                                             

Text Box: IGF-1Longevity

 

 

          

 

                                              

Text Box: IRS1 Text Box: Vegf Text Box: Creb
Text Box: IGF-1r Text Box: P13k
 


                                                                    

                           

   2007/8-1/29                                                         

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]

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]