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.

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.

Role for Interleukin-6 and Insulin like Growth Factor-I Via PI3-K/Akt Pathway in the Proliferation of CD56-Negative and Positive Multiple Myeloma Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3365-3365
Author(s):  
Naohi Sahara ◽  
Akihiro Takeshita ◽  
Miki Kobayashi ◽  
Kazuyuki Shigeno ◽  
Satoki Nakamura ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
Cyclin D1 ◽  
Cell Lines ◽  
Interleukin 6 ◽  
Akt Pathway ◽  
Insulin Like Growth Factor ◽  
Ki 67 ◽  
Factor I ◽  
Igf I

Abstract Several studies including ours have suggested that lack of CD56 expression in multiple myeloma (MM) defines a unique patient subset with poorer prognosis. However, the mechanism underlying this aggressive behavior of CD56− MM has not been well elucidated. In this study, we sorted out both CD56− and CD56+ fractions from MM cell lines or patients with MM, and investigated their different responsiveness to interleukin-6 (IL-6) or insulin like growth factor-I (IGF-I), and tried to clarify the course of action in cell cycle distribution. After stained with PE-CD56, CD56− and CD56+ fractions in KMS-21-BM and U-266 cell lines were isolated by the cell sorter, and cultured separately either in the presence or absence of IL-6 (2 ng/ml and 10 ng/ml, respectively). Although CD56− cells in both KMS-21-BM and U-266 cell lines responded significantly to IL-6 (P=0.001 and 0.009, respectively), CD56+ cells did not. Ki-67+ cells in CD56− KMS-21-BM cells, that were significantly fewer than that in CD56+ ones (P=0.0003), increased significantly upon 24-hour incubation with IL-6 (P<0.0001). Western blotting analysis showed that the level of cyclin D1 and p27 protein in CD56− KMS-21-BM cells were up- and down-regulated by IL-6 in a time dependent manner, respectively. IL-6 also brought phosphorylation of Akt (ser473) in the CD56− cells. LY-294002 completely blocked these effects of IL-6. On the other hand, Ki-67+ cells in the CD56+ cells did not respond to IL-6. Although IGF-I did not increase Ki-67+ cells either in the CD56− and CD56+ cells from KMS-21-BM, anti-IGF-I mAb significantly reduced Ki-67+ cells only in the CD56+ cells (P=0.006). IGF-I up-regulated the level of cyclin D1 and phosphorylated Akt in CD56+ KMS-21-BM cells. LY294002 completely blocked these effects of IGF-I. Same results were obtained in the analysis of U-266 cell lines. The MM cells sorted from 17 patients with MM were also examined for CD56 and Ki-67 expression. Four and 13 patients were distributed to the CD56− and CD56+ group, respectively. These MM cells from the patients were cultured with or without IL-6 (10 ng/ml) or IGF-I (500ng/ml) for 24 hours. IL-6 increased the percentage of Ki-67+ cells in the CD56− group more than those in the CD56+ group (P=0.007). Although MM cells did not respond to IL-6, IGF-I significantly increased Ki-67+ cells in the CD56+ group (P=0.005). These results suggest that CD56− and CD56+ MM cells could be stimulated by different cytokines. We here found that CD56− MM cells were proliferated more than CD56+ MM cells in the presence of IL-6, and that this effect of IL-6 was mainly mediated by the activation of PI3-K/Akt pathway. In addition, our results suggest that IGF-I play an important role in the proliferation of CD56+ MM cells via PI3-K/Akt pathway.

scholarly journals Activation of the phosphatidylinositol-3' kinase pathway and DNA synthesis by a mutant insulin-like growth factor I receptor lacking the NPXY motif

2004 ◽  
Vol 181 (1) ◽  
pp. 139-146 ◽  
Author(s):  
K Kataoka ◽  
D Yu ◽  
M Miura
Keyword(s):  
Growth Factor ◽  
Dna Synthesis ◽  
Cell Lines ◽  
Insulin Like Growth Factor ◽  
Phosphatidylinositol 3 Kinase ◽  
Factor I ◽  
Igf I ◽  
Npxy Motif ◽  
Growth Factor I ◽  
Phosphatidylinositol 3

We have investigated the role of the NPXY motif in the insulin-like growth factor I receptor (IGF-IR) by focusing on the activation of the phosphatidylinositol-3' kinase (PI3-K) pathway and DNA synthesis following IGF-I stimulation. For this purpose, we established stable R-cell lines, which are deficient in endogenous IGF-IR, and express human IGF-IR lacking the whole NPEY(950) sequence (DeltaNPEY). The DeltaNPEY cells showed an apparent autophosphorylation of IGF-IR, albeit with reduced sensitivity to stimulation compared with cells expressing similar levels of wild-type IGF-IR. Activation of insulin receptor substrate (IRS)-1 and IRS-2 was severely impaired in DeltaNPEY cells even at high concentrations of IGF-I. However, recruitment of p85, a regulatory subunit of PI3-K, to activated IRS-2 was similar between the cell lines, but recruitment of p85 to IRS-1 was reduced in DeltaNPEY cells. Essentially similar levels of p85- or phosphotyrosine-associated PI3-K and Akt activities were observed between the cell lines, although the sensitivity to stimulation was reduced in DeltaNPEY cells. Activation of extracellular signal-regulated kinase and DNA synthesis were virtually unaffected by the mutation, in terms of both sensitivity to stimulation and responsiveness. DNA synthesis was completely inhibited by the PI3-K inhibitor, LY294002. These results indicate that the IGF-IR is able to activate the PI3-K pathway and induce DNA synthesis in a normal fashion without the NPXY motif when the receptor is fully activated.

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

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 (IGF-I) Prevents Amphotericin B (AmpB)-induced Apoptosis in Renal Cell Lines • 1699

1997 ◽  
Vol 41 ◽  
pp. 286-286
Author(s):  
Despina E. Varlam ◽  
Mustafa M. Siddiq ◽  
Stuart Horowitz ◽  
Frederick J. Kaskel ◽  
Lance A. Parton
Keyword(s):  
Growth Factor ◽  
Amphotericin B ◽  
Cell Lines ◽  
Renal Cell ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I ◽  
Induced Apoptosis ◽  
Renal Cell Lines

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.

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