Dominant negative PDGF-C inhibits growth of Ewing family tumor cell lines

Zwerner, Jeffrey P.; May, Win

doi:10.1038/sj.onc.1205486

Cited by 50 publications

(33 citation statements)

References 39 publications

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“…A VEGF trap is effective in the treatment of angiogenesis-related diseases such as tumor-and age-related macular degeneration (Holash et al, 2002;Nguyen et al, 2006), and Etanercept, which traps TNF␣, is used to treat rheumatoid arthritis (Goldenberg, 1999;Mohler et al, 1993). The soluble ectodomains of receptors of many other growth factors, such as IGF-I (Hongo et al, 2003), GDNF (Cerchia et al, 2003), PDGF (Borkham-Kamphorst et al, 2004;Zwerner and May, 2002) and Eph (Brantley et al, 2002;Dobrzanski et al, 2004), have also been reported to be effective in suppressing the function of their cognate growth factors by competing for binding to soluble growth factors. The MK-TRAP fragment presented in this study may represent a clinically applicable trapping reagent for cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

Midkine and LDL-receptor-related protein 1 contribute to the anchorage-independent cell growth of cancer cells

Chen

Takei

et al. 2007

Journal of Cell Science

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The growth factor midkine (MK) is highly associated with cancer progression. Knockdown of MK expression strikingly suppresses tumor growth in nude mice. Thus, MK is a candidate target for cancer treatment. LDL-receptor-related protein 1 (LRP1) is a receptor for MK. We found that among the four ligand-binding domains of LRP1, the N-terminal half of the second domain (designated as MK-TRAP) had the strongest affinity to MK. MK-TRAP bound to MK, but not to HB-GAM/pleiotrophin, basic fibroblast growth factor or platelet-derived growth factor (PDGF)-BB. Exogenous MK-TRAP inhibited the binding between MK and LRP1. G401 cells that transiently or stably overexpress MK-TRAP showed decreased cell growth in monolayer culture and reduced colony formation in soft agar, which could be rescued by exogenous MK administration. MK-TRAP collected from conditioned medium also inhibited anchorage-independent growth of G401 cells and CMT-93 cells. Anti-MK antibody also inhibited the anchorage-independent growth. CMT-93 cells stably expressing MK-TRAP formed smaller tumors in a xenograft nude mouse model than control cells. Moreover, GST-RAP, a potent inhibitor of LRP1, inhibited the anchorage-independent growth of control G401 cells but not that of MK-TRAP stable transformants. Collectively, these data demonstrate a crucial role of MK-LRP1 signaling in anchorage-independent cell growth.

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Section: Discussionmentioning

confidence: 99%

Midkine and LDL-receptor-related protein 1 contribute to the anchorage-independent cell growth of cancer cells

Chen

Takei

et al. 2007

Journal of Cell Science

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“…Numerous studies have investigated the biological roles of PDGF-C since its discovery 4 years ago (5)(6)(7)(8)(9)(10)(11)(12)(17)(18)(19)(20)(21)(22)(23). However, to date there are no reports of the functional characterization of the PDGF-C promoter in any cell type.…”

Section: Putative Binding Sites In the Human Pdgf-c Promoter-mentioning

confidence: 99%

Fibroblast Growth Factor-2 Induction of Platelet-derived Growth Factor-C Chain Transcription in Vascular Smooth Muscle Cells Is ERK-dependent but Not JNK-dependent and Mediated by Egr-1

Midgley

Khachigian

2004

Journal of Biological Chemistry

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Platelet-derived growth factors (PDGFs) play an integral role in normal tissue growth and maintenance as well as many human pathological states including atherosclerosis, fibrosis, and tumorigenesis. The PDGF family of ligands is comprised of A, B, C, and D chains. Here, we provide the first functional characterization of the PDGF-C promoter. We examined 797 bp of the human PDGF-C promoter and identified several putative recognition elements for Sp1, Ets Egr-1, and Smad. The proximal region of the PDGF-C promoter bears a remarkable resemblance to a comparable region of the PDGF-A promoter (1). Binding and transient transfection analysis in primary vascular smooth muscle cells revealed that PDGF-C, like PDGF-A, is under the transcriptional control of the zinc finger nuclear protein Egr-1 (early growth response-1). Electrophoretic mobility shift analysis using both smooth muscle cell nuclear extracts and recombinant protein revealed that Egr-1 and Sp1 bind this region of the PDGF-C promoter (Oligo C, ؊35 to ؊1). Egr-1 competes with Sp1 for overlapping binding sites even when the former is at a stoichiometric disadvantage. Reverse transcriptase PCR and supershift analysis demonstrate that fibroblast growth factor-2 (FGF-2) stimulates both Egr-1 and PDGF-C mRNA expression in a time-dependent and transient manner and that FGF-2-inducible Egr-1 binds the proximal PDGF-C promoter. FGF-2-inducible PDGF-C expression was completely abrogated using catalytic DNA (DNAzymes) targeting Egr-1 but not by its scrambled counterpart. Moreover, using pharmacological inhibitors we demonstrate the critical role of ERK but not JNK in FGF-2-inducible PDGF-C expression. These findings thus demonstrate that PDGF-C transcription, activated by FGF-2, is mediated by Egr-1 and its upstream kinase ERK.

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“…In detail, osteosarcoma and Ewing's sarcoma, the two most frequent bone tumors (although the cell of origin of Ewing's sarcoma has not been clearly established) usually arising in children and adolescents (3), as well as rhabdomyosarcoma, the most common soft tissue sarcoma of childhood (4), show the presence of both active IGF-IR and the autocrine production of its ligands IGF-I and/or IGF-II (5-7). Although several other growth factor circuits are involved in deregulated cell growth of these neoplasms (8)(9)(10)(11)(12), the contribution of IGF-I/IGF-IR circuit to the malignant behavior of these cells has been clearly identified as of major importance. IGF-IR is implicated in autocrine and paracrine control of sarcoma growth and seems to be particularly relevant in pathogenesis of these tumors (13)(14)(15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Antitumor Activity of the Insulin-Like Growth Factor-I Receptor Kinase Inhibitor NVP-AEW541 in Musculoskeletal Tumors

Scotlandi¹,

Manara²,

Nicoletti³

et al. 2005

Cancer Research

270

193

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Dominant negative PDGF-C inhibits growth of Ewing family tumor cell lines

Cited by 50 publications

References 39 publications

Midkine and LDL-receptor-related protein 1 contribute to the anchorage-independent cell growth of cancer cells

Midkine and LDL-receptor-related protein 1 contribute to the anchorage-independent cell growth of cancer cells

Fibroblast Growth Factor-2 Induction of Platelet-derived Growth Factor-C Chain Transcription in Vascular Smooth Muscle Cells Is ERK-dependent but Not JNK-dependent and Mediated by Egr-1

Antitumor Activity of the Insulin-Like Growth Factor-I Receptor Kinase Inhibitor NVP-AEW541 in Musculoskeletal Tumors

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