title: Decorin antagonizes IGF receptor I (IGF-IR) function by interfering with IGF-IR activity and attenuating downstream signaling.
abstract: We have recently discovered that the insulin-like growth factor receptor I (IGF-IR) is up-regulated in human invasive bladder cancer and promotes migration and invasion of transformed urothelial cells. The proteoglycan decorin, a key component of the tumor stroma, can positively regulate the IGF-IR system in normal cells. However, there are no available data on the role of decorin in modulating IGF-IR activity in transformed cells or in tumor models. Here we show that the expression of decorin inversely correlated with IGF-IR expression in low and high grade bladder cancers (n = 20 each). Decorin bound with high affinity IGF-IR and IGF-I at distinct sites and negatively regulated IGF-IR activity in urothelial cancer cells. Nanomolar concentrations of decorin promoted down-regulation of IRS-1, one of the critical proteins of the IGF-IR pathway, and attenuated IGF-I-dependent activation of Akt and MAPK. This led to decorin-evoked inhibition of migration and invasion upon IGF-I stimulation. Notably, decorin did not cause down-regulation of the IGF-IR in bladder, breast, and squamous carcinoma cells. This indicates that decorin action on the IGF-IR differs from its known activity on other receptor tyrosine kinases such as the EGF receptor and Met. Our results provide a novel mechanism for decorin in negatively modulating both IGF-I and its receptor. Thus, decorin loss may contribute to increased IGF-IR activity in the progression of bladder cancer and perhaps other forms of cancer where IGF-IR plays a role.
authors.affiliation: Department Pathology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. iozzo@kimmelcancercenter.org
authors.forename: Renato V
authors.initials: RV
authors.lastname: Iozzo
authors.forename: Simone
authors.initials: S
authors.lastname: Buraschi
authors.forename: Marco
authors.initials: M
authors.lastname: Genua
authors.forename: Shi-Qiong
authors.initials: SQ
authors.lastname: Xu
authors.forename: Charalambos C
authors.initials: CC
authors.lastname: Solomides
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Peiper
authors.forename: Leonard G
authors.initials: LG
authors.lastname: Gomella
authors.forename: Rick C
authors.initials: RC
authors.lastname: Owens
authors.forename: Andrea
authors.initials: A
authors.lastname: Morrione
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D058575:Decorin / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D036341:Intercellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D001749:Urinary Bladder Neoplasms / Q000378:metabolism
chemical_list: D058575:Decorin; D036341:Intercellular Signaling Peptides and Proteins; D017526:Receptor, IGF Type 1