Integrin-mediated action of insulin-like growth factor binding protein-2 in tumor cells

Abstract

The neoplastic production of the insulin-like growth factor binding protein (IGFBP)-2 often correlates with tumor malignancy and aggressiveness. Since IGFBP-2 contains an RGD motif in its C-terminus, it was hypothesized that this protein may act independently of IGF on tumor cells through integrins. To investigate this, integrin binding, intracellular signaling and the impact of IGFBP-2 on cell adhesion and proliferation were examined in two tumor cell lines. In tracer displacement studies, up to 30% of the added 125 I-hIGFBP-2 specifically bound to the cells. Bound 125 I-hIGFBP-2 was reversibly displaced by IGFBP-2, IGFBP-1 and RGD-(Gly-Arg-Asp)-containing peptides, but not by IGFBP-3, -4, -5, -6 and RGE-(Gly-Arg-Glu)-containing peptides. Blocking with antibodies directed against different integrins and with fibronectin demonstrated that IGFBP-2 cell surface binding is specific for 5 1-integrin. Incubation of IGFBP-2 with equimolar quantities of IGF-I and IGF-II annihilated RGD-specific binding. IGFBP-2 binding at the cell surface led to dephosphorylation of the focal adhesion-kinase (FAK) of up to 37% (P<0·01), and of the p42/44 MAP-kinases of up to 40% (P<0·01). In addition, IGFBP-2 promoted de-adhesion of the cells dose-dependently by up to 30% (P<0·05), and reduced proliferation by 24% (P<0·01). Since one of the cell lines used does not express a functional IGF-I receptor, these data demonstrate that IGFBP-2 can act in an IGF-independent manner, at least in part by an interaction with 5 1-integrin.

Ex vivo expansion of hematopoietic stem cells

“…These results are accordant with the reported role of nephroblastoma overexpressed (CCN3/NOV), an IGFBP domain-containing protein, which supports expansion of human HSCs [149]. Multiple membrane proteins, including cell surface integrins [139,[142][143][144], Frizzle 8, and low-density lipoprotein (LDL) receptor-related protein 6 [150], were shown to mediate the IGF-independent effects of IGFBP2. Interestingly, extrinsic IGFBP2 can also be taken up into the cytosols of oxidative stressed cells [143,145].…”

“…While IGFBP2 exhibits IGF-dependent inhibitory effects on growth of many types of cells [137], it also displays IGF-independent activities [69,70,[138][139][140][141][142][143][144][145][146]. We identified IGFBP2 from a cancerous cell line as a supportive secreted factor for mouse and human HSCs [69,147].…”

Activity of the multikinase inhibitor dasatinib against ovarian cancer cells

“…Recent data support this hypothesis, in that IGFBP2 was shown to independently promote cell mobility through its interaction with integrins (Schütt et al, 2004;Wang et al, 2006). Moreover, IGFBP2 has been described to be a candidate biomarker for PTEN status and PI3K/Akt pathway activation (Mehrian-Shai et al, 2007).…”

Gene expression profiling identifies potential relevant genes in alveolar rhabdomyosarcoma pathogenesis and discriminates PAX3‐FKHR positive and negative tumors

“…This interaction seems to affect cell proliferation and adhesion, thus contributing to tumor cell dissemination and progression. 65 FIGURE 5 -Complete validation procedure. Predictive classification accuracy (ATE) with 95% confidence interval versus increasing number of features using real (decreasing line) and random class (upper line) labels.…”