Martin JL, Baxter RCSignalling pathways of insulin-like growth factors (IGFs) and IGF binding protein-3. Growth Factors 29(6): 235-244
Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St Leonards, Australia. Growth factors (Chur, Switzerland)
(Impact Factor: 3.39).
09/2011; 29(6):235-44. DOI: 10.3109/08977194.2011.614237
Although the insulin-like growth factor (IGF) system is essential for normal growth and development, its dysregulation has been implicated in a range of pathological states. The peptide growth factors IGF-I and IGF-II exert their effects by binding to cell-surface heterotetrameric tyrosine kinase receptors and activating multiple intracellular signalling cascades, leading to changes in the expression of proteins essential for cell proliferation, survival and differentiation. The IGF system comprises multiple ligands, receptors and high-affinity IGF binding proteins (IGFBPs), with added complexity arising from crosstalk between its receptors and other key growth-regulatory pathways such as those activated by steroid hormones, integrins and other receptor tyrosine kinases. The IGFBPs are also increasingly recognised for their intrinsic growth-regulatory activity, and the ability of IGFBP-3 to modulate signalling pathways of nuclear hormone and growth factor receptors, as well as novel receptors, is believed to play a role both in normal physiology and in disease.
Available from: Weiya Xia
- "The regulation of IGF-IR signaling is complex and not yet fully understood; however, it is well established that the IGF-IR signaling axis can be dysregulated by altered expression of the IGF ligands and IGF-binding proteins. The insulin-like growth factor binding protein-3 (IGFBP3) is the major binding protein and regulator of IGF-1 ligand bioavailability and has been reported to inhibit as well as potentiate the activity of IGF-IR signaling in different cancers [22–24]. In the least malignant breast cancer cell lines, IGFBP3 plays an inhibitory role as a tumor suppressor, and this function is reversed in highly malignant breast cancer cells which express higher levels of IGFBP3 . "
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ABSTRACT: Brain metastasis is a common cause of mortality in cancer patients, yet potential therapeutic targets remain largely unknown. The type I insulin-like growth factor receptor (IGF-IR) is known to play a role in the progression of breast cancer and is currently being investigated in the clinical setting for various types of cancer. The present study demonstrates that IGF-IR is constitutively autophosphorylated in brain-seeking breast cancer sublines. Knockdown of IGF-IR results in a decrease of phospho-AKT and phospho-p70s6k, as well as decreased migration and invasion of MDA-MB-231Br brain-seeking cells. In addition, transient ablation of IGFBP3, which is overexpressed in brain-seeking cells, blocks IGF-IR activation. Using an in vivo experimental brain metastasis model, we show that IGF-IR knockdown brain-seeking cells have reduced potential to establish brain metastases. Finally, we demonstrate that the malignancy of brain-seeking cells is attenuated by pharmacological inhibition with picropodophyllin, an IGF-IR-specific tyrosine kinase inhibitor. Together, our data suggest that the IGF-IR is an important mediator of brain metastasis and its ablation delays the onset of brain metastases in our model system.
PLoS ONE 09/2013; 8(9):e73406. DOI:10.1371/journal.pone.0073406 · 3.23 Impact Factor
Available from: europepmc.org
- "In addition, IGF-I has been reported to play a role in several pathological conditions. Interaction with the IGF binding proteins (IGFBPs) has been shown to both enhance and attenuate actions of IGF-I . In addition, the IGFBPs are known to possess intrinsic growth regulatory activity, independent of their interactions with IGF-I. "
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ABSTRACT: Insulin-like growth factor I (IGF-I) is implicated in breast cancer development and 1, 25-dihydroxyvitamin D3 (1, 25-D3) has been shown to attenuate prosurvival effects of IGF-I on breast cancer cells. In this study the role of IGF binding protein-3 (IGFBP-3) in 1, 25-D3-induced apoptosis was investigated using parental MCF-7 breast cancer cells and MCF-7/VD(R) cells, which are resistant to the growth inhibitory effects of 1, 25-D3. Treatment with 1, 25-D3 increased IGFBP-3 mRNA expression in both cell lines but increases in intracellular IGFBP-3 protein and its secretion were observed only in MCF-7. 1, 25-D3-induced apoptosis was not associated with activation of any caspase but PARP-1 cleavage was detected in parental cells. IGFBP-3 treatment alone produced cleavage of caspases 7, 8, and 9 and PARP-1 in MCF-7 cells. IGFBP-3 failed to activate caspases in MCF-7/VD(R) cells; however PARP-1 cleavage was detected. 1, 25-D3 treatment inhibited IGF-I/Akt survival signalling in MCF-7 but not in MCF-7/VD(R) cells. In contrast, IGFBP-3 treatment was effective in inhibiting IGF-I/Akt pathways in both breast cancer lines. These results suggest a role for IGFBP-3 in 1, 25-D3 apoptotic signalling and that impaired secretion of IGFBP-3 may be involved in acquired resistance to vitamin D in breast cancer.
International Journal of Cell Biology 04/2013; 2013(6):960378. DOI:10.1155/2013/960378
Available from: Sylvie Babajko
- "endoplasmic reticulum) and dismissing the hypothesis of an IGFBP internalization-dependent mechanism. Thus, although some IGFBPs such as IGFBP-2 (for review ), IGFBP-3 (for review ) and IGFBP-6 ,  were described to have intracellular functions, the rise in intracellular calcium concentration induced by IGFBPs seems unlikely to be dependent upon their intracellular localization. It is therefore conceivable that such rapid responses occur after the IGFBP cell surface binding onto membrane receptors. "
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Insulin-like growth factor binding proteins (IGFBPs) are six related secreted proteins that share IGF-dependent and -independent functions. If the former functions begin to be well described, the latter are somewhat more difficult to investigate and to characterize. At the cellular level, IGFBPs were shown to modulate numerous processes including cell growth, differentiation and apoptosis. However, the molecular mechanisms implicated remain largely unknown. We previously demonstrated that IGFBP-3, but not IGFBP-1 or IGFBP-5, increase intracellular calcium concentration in MCF-7 cells (Ricort J-M et al. (2002) FEBS lett 527: 293–297).
We perform a global analysis in which we studied, by two different approaches, the binding of each IGFBP isoform (i.e., IGFBP-1 to -6) to the surface of two different cellular models, MCF-7 breast adenocarcinoma cells and C2 myoblast proliferative cells, as well as the IGFBP-induced increase of intracellular calcium concentration. Using both confocal fluorescence microscopy and flow cytometry analysis, we showed that all IGFBPs bind to MCF-7 cell surface. By contrast, only four IGFBPs can bind to C2 cell surface since neither IGFBP-2 nor IGFBP-4 were detected. Among the six IGFBPs tested, only IGFBP-1 did not increased intracellular calcium concentration whatever the cellular model studied. By contrast, IGFBP-2, -3, -4 and -6, in MCF-7 cells, and IGFBP-3, -5 and -6, in C2 proliferative cells, induce a rapid and transient increase in intracellular free calcium concentration. Moreover, IGFBP-2 and -3 (in MCF-7 cells) and IGFBP-5 (in C2 cells) increase intracellular free calcium concentration by a pertussis toxin sensitive signaling pathway.
Our results demonstrate that IGFBPs are able to bind to cell surface and increase intracellular calcium concentration. By characterizing the IGFBPs-induced cell responses and intracellular couplings, we highlight the cellular specificity and complexity of the IGF-independent actions of these IGF binding proteins.
PLoS ONE 03/2013; 8(3):e59323. DOI:10.1371/journal.pone.0059323 · 3.23 Impact Factor
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