Insulin-like growth factor I induces migration and invasion of human multiple myeloma cells

Blood ◽  
2004 ◽  
Vol 103 (1) ◽  
pp. 301-308 ◽  
Author(s):  
Ya-Wei Qiang ◽  
Lei Yao ◽  
Giovanna Tosato ◽  
Stuart Rudikoff
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Growth Factor ◽  
Protein Kinase ◽  
Dependent Manner ◽  
Insulin Like Growth Factor ◽  
Myeloma Cells ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

Abstract Multiple myeloma (MM) is an incurable form of cancer characterized by accumulation of malignant plasma cells in the bone marrow. During the course of this disease, tumor cells cross endothelial barriers and home to the bone marrow. In latter stages, myeloma cells extravasate through blood vessels and may seed a variety of organs. Insulin-like growth factor I (IGF-I) is one of several growth factors shown to promote the growth of MM cells. In the current study, we have assessed the ability of IGF-I to serve additionally as a chemotactic factor affecting the mobility and invasive properties of these cells. Results indicate that IGF-I promotes transmigration through vascular endothelial cells and bone marrow stromal cell lines. Analysis of endogenous signaling pathways revealed that protein kinase D/protein kinase Cμ (PKD/PKCμ) and RhoA were both activated in a phosphatidylinositol 3-kinase (PI-3K)–dependent manner. Inhibition of PI-3K, PKCs, or Rho-associated kinase by pharmacologic inhibitors abrogated migration, whereas mitogen-activated protein kinase (MAPK), Akt, and p70S6 kinase inhibitors had no effect. These results suggest that IGF-I promotes myeloma cell migration by activation of PI-3K/PKCμ and PI-3K/RhoA pathways independent of Akt. The identification of IGF-I as both a proliferative and migratory factor provides a rational basis for the development of targeted therapeutic strategies directed at IGF-I in the treatment of MM.

scholarly journals The insulin-like growth factor-I receptor inhibitor NVP-AEW541 provokes cell cycle arrest and apoptosis in multiple myeloma cells

2008 ◽  
Vol 141 (4) ◽  
pp. 470-482 ◽  
Author(s):  
Patricia Maiso ◽  
Enrique M. Ocio ◽  
Mercedes Garayoa ◽  
Juan C. Montero ◽  
Francesco Hofmann ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Growth Factor ◽  
Cell Cycle Arrest ◽  
Insulin Like Growth Factor ◽  
Myeloma Cells ◽  
Factor I ◽  
Cycle Arrest ◽  
Growth Factor I ◽  
Receptor Inhibitor

scholarly journals Evidence for modulation of osteocalcin containing gamma-carboxyglutamic acid residues synthesis by insulin-like growth factor-I and vitamin K2 in human osteosarcoma cell line MG-63

1998 ◽  
pp. 443-448 ◽  
Author(s):  
Y Kudo ◽  
M Iwashita ◽  
Y Takeda ◽  
T Muraki
Keyword(s):  
Growth Factor ◽  
Vitamin K2 ◽  
Osteosarcoma Cell ◽  
Dependent Manner ◽  
Insulin Like Growth Factor ◽  
Concentration Dependent Manner ◽  
Factor I ◽  
Carboxyglutamic Acid ◽  
Igf I ◽  
Growth Factor I

The effect of insulin-like growth factor-I (IGF-I) and 2-methyl-3-all-trans-tetraphenyl-1,4-naphtoquinone (vitamin K2) on the synthesis of osteocalcin containing gamma-carboxyglutamic acid (Gla) residues which is the physiologically relevant form in bone metabolism was studied in cultured human osteoblast-like (MG-63) cells. Both IGF-I and vitamin K2 stimulated 1,25-dihydroxyvitamin D3 (1,25(OH)2D3)-induced osteocalcin containing Gla secretion in a concentration-dependent manner. This stimulatory effect of IGF-I and vitamin K2 was additive. Vitamin K2-enhanced osteocalcin containing Gla secretion was selectively suppressed by 3-(alpha-acetonyl-benzyl)-4-hydroxy-coumarin (warfarin). The stimulatory effect of IGF-I was completely abolished by the presence of cycloheximide; in contrast the effect of vitamin K2 was still observed in the presence of cycloheximide. Treatment of MG-63 cells with IGF-I caused an approximately 2.2-fold increase in osteocalcin mRNA levels (determined by reverse transcription-polymerase chain reaction). Vitamin K2 had no effect on either the stimulation of mRNA level by IGF-I or the basal level. IGF-I-stimulated osteocalcin containing Gla secretion was inhibited by one of its binding proteins (insulin-like growth factor binding protein-4) in a concentration-dependent manner. These findings suggest that the modes of action of IGF-I and vitamin K2 on 1.25(OH)2D3-induced osteocalcin containing Gla secretion in MG-63 cells are different.

Effects of insulin-like growth factor-I and insulin on the in-vitro uptake of sulphate by eel branchial cartilage: evidence for the presence of independent hepatic and pancreatic sulphation factors

1992 ◽  
Vol 133 (2) ◽  
pp. 211-219 ◽  
Author(s):  
C. Duan ◽  
T. Hirano
Keyword(s):  
Growth Factor ◽  
Coho Salmon ◽  
Bovine Insulin ◽  
Dependent Manner ◽  
Insulin Like Growth Factor ◽  
Cartilage Growth ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

ABSTRACT The possible roles of insulin-like growth factor-I (IGF-I) and insulin in regulating cartilage growth were studied in the teleost Anguilla japonica. Significant sulphation activity was found in the extracts of pancreas, liver and muscle, but not in those of kidney, intestine or spleen. The hepatic sulphation activity was significantly decreased by hypophysectomy or by fasting for 14 days, suggesting that this activity is regulated by pituitary function and nutritional status. Northern blot analysis revealed that the hepatic IGF-I mRNA in the eel consists of a major 4·0 kb band. This mRNA was GH-dependent and was significantly decreased by fasting for 14 days. On the other hand, fasting for 14 days had no significant effect on pancreatic sulphation activity. Pancreatic extracts from both intact and hypophysectomized eels exhibited equally significant stimulating activity. Addition of bovine or human insulin (1–250 ng/ml) to the culture medium significantly stimulated sulphate uptake in a dose-dependent manner. Teleost (coho salmon) insulin was as effective as bovine insulin. Bovine insulin was more effective than IGF-I at lower concentrations (1–4 ng/ml) but less effective at higher concentrations (10–250 ng/ml). These results indicate that not only IGF-I but also insulin are likely to be involved in the regulation of cartilage growth in the eel. Journal of Endocrinology (1992) 133, 211–219

Insulin-like growth factor I is a dual effector of multiple myeloma cell growth

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2856-2861 ◽  
Author(s):  
Nie-Lin Ge ◽  
Stuart Rudikoff
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
Cell Growth ◽  
Myeloma Cell ◽  
Mitogen Activated Protein Kinase ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

Abstract Multiple myeloma (MM) is an invariably fatal disease that accounts for approximately 1% to 2% of all human cancers. Surprisingly little is known about the cellular pathways contributing to growth of these tumors. Although the cytokine interleukin-6 has been suggested to be the major stimulus for myeloma cell growth, the role of a second potential growth factor, insulin-like growth factor I (IGF-I), has been less clearly defined. The IGF-I signaling cascade in 8 MM cell lines was examined. In 7 of these, the IGF-I receptor (IGF-IR) was expressed and autophosphorylated in response to ligand. Downstream of IGF-IR, insulin receptor substrate 1 was phosphorylated, leading to the activation of phosphatidylinositol-3′-kinase (PI-3K). PI-3K, in turn, regulated 2 distinct pathways. The first included Akt and Bad, leading to an inhibition of apoptosis; the second included the mitogen-activated protein kinase (MAPK), resulting in proliferation. Biologic relevance of this pathway was demonstrated because in vitro IGF-I induced both an antiapoptotic and a proliferative effect. Importantly, in vivo administration of IGF-I in SCID mice inoculated with the OPM-2 line led to approximately twice the growth rate of tumor cells as in controls. These results suggest that IGF-I activates at least 2 pathways effecting myeloma cell growth and contributes significantly to expansion of these cells in vivo.

scholarly journals Insulin-like growth factor I and insulin induce adipogenic-related gene expression in fetal brown adipocyte primary cultures

1996 ◽  
Vol 319 (2) ◽  
pp. 627-632 ◽  
Author(s):  
Teresa TERUEL ◽  
Angela M VALVERDE ◽  
Manuel BENITO ◽  
Margarita LORENZO
Keyword(s):  
Growth Factor ◽  
Fatty Acid Synthase ◽  
Brown Adipocyte ◽  
Dependent Manner ◽  
Insulin Like Growth Factor ◽  
Brown Adipocytes ◽  
Factor I ◽  
Fetal Rat ◽  
Igf I ◽  
Growth Factor I

Fetal rat brown adipocytes show high-affinity binding sites for both insulin-like growth factor I (IGF-I) and insulin. Cell culture for 24 h in the presence of IGF-I or insulin, independently, up-regulated the mRNA expression of adipogenic-related genes, such as fatty acid synthase (FAS), glycerol-3-phosphate dehydrogenase and insulin-regulated glucose transporter Glut4, and down-regulated the expression of phosphoenolpyruvate carboxykinase mRNA in a dose-dependent manner. Moreover, both IGF-I and insulin increased the FAS gene transcription rate at 2 h, producing a time-dependent accumulation of FAS mRNA. Furthermore IGF-I or insulin increased glucose uptake and lipid content throughout the 24 h culture period. Our results suggest that both IGF-I and insulin are major signals involved in initiating and/or maintaining the expression of adipogenic-related genes in fetal rat brown adipocytes.

scholarly journals RACK1, an Insulin-Like Growth Factor I (IGF-I) Receptor-Interacting Protein, Modulates IGF-I-Dependent Integrin Signaling and Promotes Cell Spreading and Contact with Extracellular Matrix

2002 ◽  
Vol 22 (7) ◽  
pp. 2345-2365 ◽  
Author(s):  
Ulrich Hermanto ◽  
Cong S. Zong ◽  
Weiqun Li ◽  
Lu-Hai Wang
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Protein Kinase ◽  
Focal Adhesion ◽  
Cell Spreading ◽  
Β1 Integrin ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

ABSTRACT The insulin-like growth factor I (IGF-I) receptor (IGF-IR) is known to regulate a variety of cellular processes including cell proliferation, cell survival, cell differentiation, and cell transformation. IRS-1 and Shc, substrates of the IGF-IR, are known to mediate IGF-IR signaling pathways such as those of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K), which are believed to play important roles in some of the IGF-IR-dependent biological functions. We used the cytoplasmic domain of IGF-IR in a yeast two-hybrid interaction trap to identify IGF-IR-interacting molecules that may potentially mediate IGF-IR-regulated functions. We identified RACK1, a WD repeat family member and a Gβ homologue, and demonstrated that RACK1 interacts with the IGF-IR but not with the closely related insulin receptor (IR). In several types of mammalian cells, RACK1 interacted with IGF-IR, protein kinase C, and β1 integrin in response to IGF-I and phorbol 12-myristate 13-acetate stimulation. Whereas most of RACK1 resides in the cytoskeletal compartment of the cytoplasm, transformation of fibroblasts and epithelial cells by v-Src, oncogenic IR or oncogenic IGF-IR, but not by Ros or Ras, resulted in a significantly increased association of RACK1 with the membrane. We examined the role of RACK1 in IGF-IR-mediated functions by stably overexpressing RACK1 in NIH 3T3 cells that expressed an elevated level of IGF-IR. RACK1 overexpression resulted in reduced IGF-I-induced cell growth in both anchorage-dependent and anchorage-independent conditions. Overexpression of RACK1 also led to enhanced cell spreading, increased stress fibers, and increased focal adhesions, which were accompanied by increased tyrosine phosphorylation of focal adhesion kinase and paxillin. While IGF-I-induced activation of IRS-1, Shc, PI3K, and MAPK pathways was unaffected, IGF-I-inducible β1 integrin-associated kinase activity and association of Crk with p130CAS were significantly inhibited by RACK1 overexpression. In RACK1-overexpressing cells, delayed cell cycle progression in G1 or G1/S was correlated with retinoblastoma protein hypophophorylation, increased levels of p21Cip1/WAF1 and p27Kip1, and reduced IGF-I-inducible Cdk2 activity. Reduction of RACK1 protein expression by antisense oligonucleotides prevented cell spreading and suppressed IGF-I-dependent monolayer growth. Our data suggest that RACK1 is a novel IGF-IR signaling molecule that functions as a positive mediator of cell spreading and contact with extracellular matrix, possibly through a novel IGF-IR signaling pathway involving integrin and focal adhesion signaling molecules.

scholarly journals Insulin-like growth factor I is a growth and survival factor in human multiple myeloma cell lines

Blood ◽  
1996 ◽  
Vol 88 (6) ◽  
pp. 2250-2258 ◽  
Author(s):  
P Georgii-Hemming ◽  
HJ Wiklund ◽  
O Ljunggren ◽  
K Nilsson
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
Cell Lines ◽  
Insulin Like Growth Factor ◽  
Growth And Survival ◽  
Factor I ◽  
Survival Factor ◽  
Igf I ◽  
Human Multiple Myeloma ◽  
Growth Factor I

Human multiple myeloma (MM) represents a highly aneuploid tumor as shown by cytogenetic studies. This may partly explain the heterogeneity with regard to growth factor requirements demonstrated among MM cells. We have previously reported the expression of insulin-like growth factor I (IGF-I) and IGF-I receptor (IGF-IR) mRNA in some MM cell lines. In this study we investigated the role of IGF-I as a growth and/or survival factor in three MM cell lines: LP-1, EJM, and Karpas 707. We report that all cell lines expressed IGF-I and IGF-IR mRNA and protein. LP-1 and Karpas 707, but not EJM, were stimulated to proliferation in a dose-dependent manner by exogenous IGF-I. An IGF-IR blocking antibody inhibited both the IGF-I-induced and spontaneous growth of LP-1, and Karpas 707, while the EJM cell line was unaffected by the addition of the antibody. In conclusion, our results show that IGF-I can act as a growth factor in human MM, and they suggest that an autocrine IGF-I loop may contribute to the growth and survival in some MM cell lines.

Receptor synergy of interleukin-6 (IL-6) and insulin-like growth factor-I in myeloma cells that highly express IL-6 receptor α

Blood ◽  
2004 ◽  
Vol 103 (6) ◽  
pp. 2291-2298 ◽  
Author(s):  
Saeid Abroun ◽  
Hideaki Ishikawa ◽  
Naohiro Tsuyama ◽  
Shangqin Liu ◽  
Fu-Jun Li ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Line ◽  
Interleukin 6 ◽  
Janus Kinase ◽  
Insulin Like Growth Factor ◽  
Myeloma Cells ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I ◽  
Human Myeloma Cells

Abstract Interleukin-6 (IL-6) is a growth and antiapoptotic factor for human myeloma cells. The autocrine loop and increased expression of the growth factor receptors have been postulated as the mechanisms of tumorigenesis. Here we show that IL-6 stimulation induced the phosphorylation of insulin-like growth factor-I (IGF-I) receptors in a human myeloma cell line, NOP2, highly expressing IL-6 receptor α (IL-6Rα) and in the IL-6Rα–transfected U266 cell line. IL-6–dependent complex formation of IL-6Rα with IGF-I receptor β was found in NOP2 where IL-6Rα colocalized with IGF-I receptors at lipid rafts. Moreover, the IL-6–induced phosphorylation of IGF-I receptor β was not blocked by a Janus kinase 2 (Jak2) inhibitor. In addition to the activation of the signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2, IL-6 stimulation led to the activation of Akt, presumably following the phosphorylation of IGF-I receptors. Thus, our results suggest that in NOP2, IL-6Rα and IGF-I receptors exist on the plasma membrane in close proximity, facilitating the efficient assembly of 2 receptors in response to IL-6. The synergistic effects of highly expressed IL-6Rα on IGF-I receptor–mediated signals provide a novel insight into the Jak-independent IL-6 signaling mechanism of receptor cross-talk in human myeloma cells.

scholarly journals Gq-coupled Purinergic Receptors Inhibit Insulin-like Growth Factor-I/Phosphoinositide 3-Kinase Pathway-dependent Keratinocyte Migration

2010 ◽  
Vol 21 (6) ◽  
pp. 946-955 ◽  
Author(s):  
Salma Taboubi ◽  
Françoise Garrouste ◽  
Fabrice Parat ◽  
Gilbert Pommier ◽  
Emilie Faure ◽  
...  
Keyword(s):  
Growth Factor ◽  
Purinergic Receptors ◽  
Purinergic Signaling ◽  
Extracellular Nucleotides ◽  
Dependent Manner ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Keratinocyte Migration ◽  
Igf I ◽  
Growth Factor I

Insulin-like growth factor-I (IGF-I) activation of phosphoinositol 3-kinase (PI3K) is an essential pathway for keratinocyte migration that is required for epidermis wound healing. We have previously reported that activation of Gα(q/11)-coupled-P2Y2purinergic receptors by extracellular nucleotides delays keratinocyte wound closure. Here, we report that activation of P2Y2receptors by extracellular UTP inhibits the IGF-I–induced p110α-PI3K activation. Using siRNA and pharmacological inhibitors, we demonstrate that the UTP antagonistic effects on PI3K pathway are mediated by Gα(q/11)—and not G(i/o)—independently of phospholipase Cβ. Purinergic signaling does not affect the formation of the IGF-I receptor/insulin receptor substrate-I/p85 complex, but blocks the activity of a membrane-targeted active p110α mutant, indicating that UTP acts downstream of PI3K membrane recruitment. UTP was also found to efficiently attenuate, within few minutes, the IGF-I–induced PI3K-controlled translocation of the actin-nucleating protein cortactin to the plasma membrane. This supports the UTP ability to alter later migratory events. Indeed, UTP inhibits keratinocyte spreading and migration promoted by either IGF-I or a membrane-targeted active p110α mutant, in a Gα(q/11)-dependent manner both. These findings provide new insight into the signaling cross-talk between receptor tyrosine kinase and Gα(q/11)-coupled receptors, which mediate opposite effects on p110α-PI3K activity and keratinocyte migration.

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