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TGF-β-induced expression of IGFBP-3 regulates IGF1R signaling in human osteosarcoma cells

Lynette J Schedlich1, Vanessa M Yenson, Robert C Baxter

  • 1Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, Sydney, NSW 2065, Australia. lyn.schedlich@sydney.edu.au

Molecular and Cellular Endocrinology
|July 9, 2013
PubMed

Insights

Transforming growth factor-β (TGF-β) signaling induces insulin-like growth factor binding protein-3 (IGFBP-3) in osteosarcoma cells. This IGFBP-3 then inhibits cell growth by negatively regulating the type I IGF receptor (IGF1R) pathway.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Cancer Research

Background:

  • Transforming growth factor-β (TGF-β) and insulin-like growth factors (IGFs) signaling pathways are crucial in osteosarcoma cell proliferation.
  • Understanding the cross-talk between these pathways is vital for developing targeted therapies.

Purpose of the Study:

  • To investigate the role of endogenous insulin-like growth factor binding protein-3 (IGFBP-3) in mediating cross-talk between TGF-β receptor and type I IGF receptor (IGF1R) signaling in MG-63 osteosarcoma cells.
  • To elucidate the regulatory mechanisms governing osteosarcoma cell growth.

Main Methods:

  • Utilized MG-63 osteosarcoma cell line.
  • Investigated the activation of Ras/Raf/MAPK pathway and expression of IGFBP-3.
  • Assessed the effects of IGFBP-3 on ERK1/2 and Akt activation.
  • Examined the impact of IGFBP-3 on cell cycle progression and proliferation.
  • Analyzed Smad2 phosphorylation and nuclear accumulation.

Main Results:

  • TGF-β1 indirectly activated the Ras/Raf/MAPK pathway and induced IGFBP-3 expression.
  • IGFBP-3 attenuated TGF-β1-induced activation of ERK1/2 and Akt, inhibiting cell cycle progression and proliferation.
  • Inhibition of IGF1R signaling blocked the effects of IGFBP-3.
  • Blocking TGF-β1-induced IGFBP-3 expression enhanced Smad2 phosphorylation and nuclear accumulation.

Conclusions:

  • TGF-β1 plays a significant role in osteosarcoma cell growth.
  • TGF-β1-induced IGFBP-3 acts as a negative-feedback mechanism to control cell growth.
  • This feedback loop functions by preventing the activation of the IGF1R pathway, thereby regulating osteosarcoma proliferation.
Keywords:
EGFHGFIGFIGF binding protein-3IGF1RIGF1R KIIGF1R kinase inhibitorIGFBP-3Insulin-like growth factorInsulin-like growth factor binding protein-3MAPKOsteosarcomaPI3-KR-SmadsRNA interferenceRNAiSAPK/JNKSignalingTGF-βTGF-β receptorTGF-β type I receptorTGF-β type II receptorTransforming growth factor-βTβRTβRITβRIIc-Jun N-terminal kinaseepidermal growth factorhepatocyte growth factorinsulin-like growth factormitogen activated protein kinasephosphoinositide 3-kinasereceptor-activated Smadstransforming growth factor-βtype I IGF receptor

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