Heparin-binding mechanism of the IGF2/IGF-binding protein 2 complex

Lund, J.; Søndergaard, Mads Toft; Conover, Cheryl A.; Overgaard, Michael Toft

doi:10.1530/jme-13-0184

Cited by 20 publications

(10 citation statements)

References 38 publications

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“…HS has been reported to regulate receptor signaling through the modulation of binding between growth factors (FGF, HGF, and IGF) and their receptors (FGFR and Met) or growth factor binding proteins. [30][31][32][36][37][38][39] Thus, we examined the effect of PAPSS2 depletion on receptor signaling pathways such as FGFR1, Met, and beta subunit of IGF-1 receptor (IGF1Rβ). In PAPSS2-depleted MCF7 cells, we observed augmented FGFR phosphorylation.…”

Section: Resultsmentioning

confidence: 99%

Heparan sulfation is essential for the prevention of cellular senescence

et al. 2015

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Cellular senescence is considered as an important tumor-suppressive mechanism. Here, we demonstrated that heparan sulfate (HS) prevents cellular senescence by fine-tuning of the fibroblast growth factor receptor (FGFR) signaling pathway. We found that depletion of 3′-phosphoadenosine 5′-phosphosulfate synthetase 2 (PAPSS2), a synthetic enzyme of the sulfur donor PAPS, led to premature cell senescence in various cancer cells and in a xenograft tumor mouse model. Sodium chlorate, a metabolic inhibitor of HS sulfation also induced a cellular senescence phenotype. p53 and p21 accumulation was essential for PAPSS2-mediated cellular senescence. Such senescence phenotypes were closely correlated with cell surface HS levels in both cancer cells and human diploid fibroblasts. The determination of the activation of receptors such as FGFR1, Met, and insulin growth factor 1 receptor β indicated that the augmented FGFR1/AKT signaling was specifically involved in premature senescence in a HS-dependent manner. Thus, blockade of either FGFR1 or AKT prohibited p53 and p21 accumulation and cell fate switched from cellular senescence to apoptosis. In particular, desulfation at the 2-O position in the HS chain contributed to the premature senescence via the augmented FGFR1 signaling. Taken together, we reveal, for the first time, that the proper status of HS is essential for the prevention of cellular senescence. These observations allowed us to hypothesize that the FGF/FGFR signaling system could initiate novel tumor defenses through regulating premature senescence.

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Section: Resultsmentioning

confidence: 99%

Heparan sulfation is essential for the prevention of cellular senescence

et al. 2015

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“…Specifically, it has been proposed that, by favoring the binding of IGF/IGFBP complexes to “heparin-like glycosaminoglycans” at the cell surface and ECM, certain IGFBPs can increase local IGF activity stimulating nearby IGF1R [59, 60]. In addition, although IGF ligands are not considered canonical heparin-binding proteins, a previously uncharacterized putative heparin-binding domain in IGF2 has been recently demonstrated to play a pivotal role in the IGF2/IGFBP2 complex affinity for heparin [61]. Overall, these studies and our present findings are consistent with interference on the formation of a functional IGF/IGFBP/HS ternary complex as mechanism of inhibition of IGF1R activation by roneparstat.…”

Section: Discussionmentioning

confidence: 99%

Antitumor efficacy of the heparan sulfate mimic roneparstat (SST0001) against sarcoma models involves multi-target inhibition of receptor tyrosine kinases

Cassinelli

Favini

et al. 2016

Oncotarget

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The heparan sulfate (HS) mimic/heparanase inhibitor roneparstat (SST0001) shows antitumor activity in preclinical sarcoma models. We hypothesized that this 100% N-acetylated and glycol-split heparin could interfere with the functions of several receptor tyrosine kinases (RTK) coexpressed in sarcomas and activated by heparin-binding growth factors. Using a phospho-proteomic approach, we investigated the drug effects on RTK activation in human cell lines representative of different sarcoma subtypes. Inhibition of FGF, IGF, ERBB and PDGF receptors by the drug was biochemically and functionally validated. Roneparstat counteracted the autocrine loop induced by the COL1A1/PDGFB fusion oncogene, expressed in a human dermatofibrosarcoma protuberans primary culture and in NIH3T3COL1A1/PDGFB transfectants, inhibiting cell anchorage-independent growth and invasion. In addition, roneparstat inhibited the activation of cell surface PDGFR and PDGFR-associated FAK, likely contributing to the reversion of NIH3T3COL1A1/PDGFB cell transformed and pro-invasive phenotype. Biochemical and histological/immunohistochemical ex vivo analyses confirmed a reduced activation of ERBB4, EGFR, INSR, IGF1R, associated with apoptosis induction and angiogenesis inhibition in a drug-treated Ewing's sarcoma family tumor xenograft. The combination of roneparstat with irinotecan significantly improved the antitumor effect against A204 rhabdoid xenografts resulting in a high rate of complete responses and cures. These findings reveal that roneparstat exerts a multi-target inhibition of RTKs relevant in the pathobiology of different sarcoma subtypes. These effects, likely cooperating with heparanase inhibition, contribute to the antitumor efficacy of the drug. The study supports heparanase/HS axis targeting as a valuable approach in combination therapies of different sarcoma subtypes providing a preclinical rationale for clinical investigation.

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“…IGFBP-3 and IGFBP-5 also undergo phosphorylation, thereby enhancing their IGF-I binding capacity [76]. Finally, the binding affinity of IGFBPs for the IGFs can be affected by the binding of IGFBPs to the cell membrane or extracellular matrix (ECM) [77]. …”

Section: The Igf Systemmentioning

confidence: 99%

The insulin-like growth factor system in multiple myeloma: diagnostic and therapeutic potential

et al. 2016

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Multiple myeloma (MM) is a highly heterogeneous plasma cell malignancy. The MM cells reside in the bone marrow (BM), where reciprocal interactions with the BM niche foster MM cell survival, proliferation, and drug resistance. As in most cancers, the insulin-like growth factor (IGF) system has been demonstrated to play a key role in the pathogenesis of MM. The IGF system consists of IGF ligands, IGF receptors, IGF binding proteins (IGFBPs), and IGFBP proteases and contributes not only to the survival, proliferation, and homing of MM cells, but also MM-associated angiogenesis and osteolysis. Furthermore, increased IGF-I receptor (IGF-IR) expression on MM cells correlates with a poor prognosis in MM patients. Despite the prominent role of the IGF system in MM, strategies targeting the IGF-IR using blocking antibodies or small molecule inhibitors have failed to translate into the clinic. However, increasing preclinical evidence indicates that IGF-I is also involved in the development of drug resistance against current standard-of-care agents against MM, including proteasome inhibitors, immunomodulatory agents, and corticoids. IGF-IR targeting has been able to overcome or revert this drug resistance in animal models, enhancing the efficacy of standard-of-care agents. This finding has generated renewed interest in the therapeutic potential of IGF-I targeting in MM. The present review provides an update of the impact of the different IGF system components in MM and discusses the diagnostic and therapeutic potentials.

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Heparin-binding mechanism of the IGF2/IGF-binding protein 2 complex

Cited by 20 publications

References 38 publications

Heparan sulfation is essential for the prevention of cellular senescence

Heparan sulfation is essential for the prevention of cellular senescence

Antitumor efficacy of the heparan sulfate mimic roneparstat (SST0001) against sarcoma models involves multi-target inhibition of receptor tyrosine kinases

The insulin-like growth factor system in multiple myeloma: diagnostic and therapeutic potential

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