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Cited by 115Multiple Myeloma Research and TreatmentsGrowth Hormone and Insulin-like Growth FactorsPI3K/AKT/mTOR signaling in cancer

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Specific roles for the PI3K and the MEK-ERK pathway in IGF-1-stimulated chemotaxis, VEGF secretion and proliferation of multiple myeloma cells: study in the 5T33MM model

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Menu, E, Kooijman, R, Valckenborgh, E Van, Asosingh, K, Bakkus, M, Camp, B Van, Vanderkerken, K·2004·British Journal of Cancer
DOI 10.1038/sj.bjc.6601613PMC PMC2409634
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Abstract

Insulin-like growth factor-1 (IGF-1) has been described as an important factor in proliferation, cell survival and migration of multiple myeloma (MM) cells. Angiogenesis correlates with development and prognosis of the MM disease. Vascular endothelial growth factor (VEGF) is one of the prominent factors involved in this process. The different functions of IGF-1 were investigated in the 5TMM mouse model with emphasis on proliferation, migration and VEGF secretion, and the signalling pathways involved. Western Blot analysis revealed that ERK1/2 and Akt (PKB) were activated after IGF-1 stimulation. The activation of ERK1/2 was reduced by the PI3K inhibitor Wortmannin, implying that the PI3K pathway is involved in its activation. Insulin-like growth factor-1 induced an increase in DNA synthesis in MM cells, which was mediated by a PI3K/Akt-MEK/ERK pathway. Insulin-like growth factor-1 enhanced F-actin assembly and this process was only PI3K mediated. Stimulation by IGF-1 of VEGF production was reduced by PD98059, indicating that only the MEK-ERK pathway is involved in IGF-1-stimulated VEGF production. In conclusion, IGF-1 mediates its multiple effects on MM cells through different signal transduction pathways. In the future, we can study the potential in vivo effects of IGF-1 inhibition on tumour growth and angiogenesis in MM.

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Figure 1 Activation of the MEK–ERK and the PI3K pathway after IGF-1 stimulation. (A) 5T33MM cells were stimulated with increasing concentrations of IGF-1 for 10 min. (B) 5T33MM cells were stimulated during different periods of time with 100 ng ml−1 IGF-1. Equivalent amounts of lysates were immunoblotted with anti-P-ERK1/2 (first panel), P-Akt (third panel), P-Jnk (fifth panel) and P-p38 (seventh panel) and reblotted with anti-ERK1/2 (second panel), anti-Akt (fourth panel), anti-JNK (sixth panel) and anti-p38 (eigth panel) to confirm equal loading. One experiment representative of four is shown.
Figure 1 Activation of the MEK–ERK and the PI3K pathway after IGF-1 stimulation. (A) 5T33MM cells were stimulated with increasing concentrations of IGF-1 for 10 min. (B) 5T33MM cells were stimulated during different periods of time with 100 ng ml−1 IGF-1. Equivalent amounts of lysates were immunoblotted with anti-P-ERK1/2 (first panel), P-Akt (third panel), P-Jnk (fifth panel) and P-p38 (seventh panel) and reblotted with anti-ERK1/2 (second panel), anti-Akt (fourth panel), anti-JNK (sixth panel) and anti-p38 (eigth panel) to confirm equal loading. One experiment representative of four is shown.CC BY · PubMed Central
Figure 2 Crosstalk between the PI3K pathway and the MEK–ERK pathway. The MEK inhibitors PD98059 and UO126 abolish stimulation by IGF-1 of ERK phosphoryation but have no influence on the phosphorylation of Akt (first and third panel). The inhibitors of the PI3K pathway Wortmannin and Ly294002, on the other hand, inhibit the phosphorylation of Akt (PKB), confirming that Akt becomes phosphorylated through activation of the PI3K pathway (third panel), but also reduces the phosphorylation of ERK1 and 2 (first panel). The cells were stimulated with 100 ng ml−1 IGF-1 for 10 min and lysates were treated as in the previous figure. One experiment representative of four is shown.
Figure 2 Crosstalk between the PI3K pathway and the MEK–ERK pathway. The MEK inhibitors PD98059 and UO126 abolish stimulation by IGF-1 of ERK phosphoryation but have no influence on the phosphorylation of Akt (first and third panel). The inhibitors of the PI3K pathway Wortmannin and Ly294002, on the other hand, inhibit the phosphorylation of Akt (PKB), confirming that Akt becomes phosphorylated through activation of the PI3K pathway (third panel), but also reduces the phosphorylation of ERK1 and 2 (first panel). The cells were stimulated with 100 ng ml−1 IGF-1 for 10 min and lysates were treated as in the previous figure. One experiment representative of four is shown.CC BY · PubMed Central
Figure 3 IGF-1 induced DNA synthesis. For the thymidine incorporation assays, the MM cells were incubated with RPMI in the absence or the presence of 10 ng ml−1 IGF-1. Before stimulation with or without IGF-1, the cells were preincubated for 30 min with Wortmannin (100 nM), PD98059 (20 μM) or both where indicated. Mean values±s.d. for four independent experiments are shown. (*: P<0.01 vs control, **: P<0.01 vs IGF-1, ***: P<0.01 vs IGF-1).
Figure 3 IGF-1 induced DNA synthesis. For the thymidine incorporation assays, the MM cells were incubated with RPMI in the absence or the presence of 10 ng ml−1 IGF-1. Before stimulation with or without IGF-1, the cells were preincubated for 30 min with Wortmannin (100 nM), PD98059 (20 μM) or both where indicated. Mean values±s.d. for four independent experiments are shown. (*: P<0.01 vs control, **: P<0.01 vs IGF-1, ***: P<0.01 vs IGF-1).CC BY · PubMed Central
Figure 4 IGF-1 induced F-actin assembly. The F-actin content of the MM cells was measured by FACS analysis. The mean fluorescence intensity is shown as the relative value compared to unstimulated cells. The cells were stimulated with or without 100ng ml−1 IGF-1, after a 30 min incubation with Wortmannin (100 nM) or PD98059 (20 μM) where indicated. The cells were then labelled with phalloidin FITC. Mean values±s.d. for three independent experiments are shown (*: P<0.02 vs control, **: P<0.04, ***: P>0.05 vs IGF-1).
Figure 4 IGF-1 induced F-actin assembly. The F-actin content of the MM cells was measured by FACS analysis. The mean fluorescence intensity is shown as the relative value compared to unstimulated cells. The cells were stimulated with or without 100ng ml−1 IGF-1, after a 30 min incubation with Wortmannin (100 nM) or PD98059 (20 μM) where indicated. The cells were then labelled with phalloidin FITC. Mean values±s.d. for three independent experiments are shown (*: P<0.02 vs control, **: P<0.04, ***: P>0.05 vs IGF-1).CC BY · PubMed Central
Figure 5 Stimulation by IGF-1 of VEGF secretion. The 5T33MM cells were stimulated with or without 100 ng ml−1 IGF-1 for 24 h, after a 30 min incubation with Wortmannin (100 nM) or PD98059 (20 μM) where indicated. Concentrations of VEGF are shown relative to unstimulated cells. The maximum IGF-1-stimulated VEGF secretion reaches 250pg ml−1. Mean values±s.d. for three independent experiments are shown (*: P<0.01 vs control, **: P<0.01, ***: P>0.05 vs 100 ng ml−1 IGF-1).
Figure 5 Stimulation by IGF-1 of VEGF secretion. The 5T33MM cells were stimulated with or without 100 ng ml−1 IGF-1 for 24 h, after a 30 min incubation with Wortmannin (100 nM) or PD98059 (20 μM) where indicated. Concentrations of VEGF are shown relative to unstimulated cells. The maximum IGF-1-stimulated VEGF secretion reaches 250pg ml−1. Mean values±s.d. for three independent experiments are shown (*: P<0.01 vs control, **: P<0.01, ***: P>0.05 vs 100 ng ml−1 IGF-1).CC BY · PubMed Central
Figure 6 IGF-1 stimulates VEGF mRNA expression. The MM cells were stimulated with 100 ng ml−1 IGF-1 for 6 or 24 h. The relative amount of VEGF in the IGF-1-stimulated samples compared to the control samples is shown. Error bars represent s.d. in the experiment. One experiment representing three is illustrated, P<0.05.
Figure 6 IGF-1 stimulates VEGF mRNA expression. The MM cells were stimulated with 100 ng ml−1 IGF-1 for 6 or 24 h. The relative amount of VEGF in the IGF-1-stimulated samples compared to the control samples is shown. Error bars represent s.d. in the experiment. One experiment representing three is illustrated, P<0.05.CC BY · PubMed Central

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Metadata

Authors
Menu, E., Kooijman, R., Valckenborgh, E. V., Asosingh, K., Bakkus, M., Camp, B. V., & Vanderkerken, K.
Affiliations
Vrije Universiteit Brussel (BE)
Corresponding author
Vanderkerken, K
ORCID
Venue
British Journal of Cancer
Publisher
Springer Science and Business Media LLC
Published
2004-03
Volume
90
Issue
5
Pages
1076-1083
ISSN
  • 0007-0920 (ISSN-L)
  • 1532-1827
DOI
10.1038/sj.bjc.6601613
PMC
PMC2409634
OpenAlex
W2049101520
Cited by
115
References
49
Citations by year
2026: 3 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 3 · 2021: 3 · 2020: 7 · 2019: 4 · 2018: 4 · 2017: 1 · 2016: 3 · 2015: 4 · 2014: 5 · 2013: 8 · 2012: 3
FWCI
6.92
Type
journal article
Language
en
Open access
Licence
Locations
  • British Journal of Cancer (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • VUBIR (Vrije Universiteit Brussel) (submittedVersion)
Funders
  • Fonds Wetenschappelijk Onderzoek
  • Vrije Universiteit Brussel
  • Vlaamse regering
Topics
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Keywords
insulin-like growth factor I, multiple myeloma, PI3K/Akt signaling, MEK/ERK signaling, VEGF secretion, cell proliferation, cell migration, angiogenesis, F-actin assembly, wortmannin, PD98059, ERK1/2 activation
MeSH terms
Animals, Cell Division, Cell Movement, Chemotaxis, Disease Models, Animal, Flavonoids, Humans, Insulin-Like Growth Factor I, Mice, Inbred C57BL, Multiple Myeloma, Neovascularization, Pathologic, Phosphorylation, Proto-Oncogene Proteins, Tumor Cells, Cultured, Signal Transduction, Down-Regulation, Protein Serine-Threonine Kinases, Phosphatidylinositol 3-Kinases, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase Kinases, Vascular Endothelial Growth Factor A, Mitogen-Activated Protein Kinase 3, Proto-Oncogene Proteins c-akt, Mice

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