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Type 1 insulin-like growth factor regulates MT1-MMP synthesis and tumor invasion via PI 3-kinase/Akt signaling

Oncogene volume 22, pages 974–982 (2003)Cite this article

Abstract

The membrane type 1 matrix metalloproteinase (MT1-MMP) has been identified as a major activator of MMP-2 – a process involving the formation of a trimolecular complex with TIMP-2. We previously identified the IGF-I receptor as a positive regulator of MMP-2 synthesis. Here, we investigated the role of IGF-IR in the regulation of MT1-MMP. Highly invasive Lewis lung carcinoma subline H-59 cells express MT1-MMP and utilize it to activate their major extracellular matrix degrading proteinase-MMP-2. These cells were transiently transfected with a plasmid vector expressing a luciferase reporter gene downstream of the mouse MT1-MMP promoter. IGF-I treatment increased luciferase activity in the transfected cells by up to 10-fold and augmented endogenous MT1-MMP mRNA and protein synthesis by up to 2–3-fold, relative to controls. MT1-MMP induction and invasion were blocked by the PI 3-kinase inhibitors LY294002 and wortmannin and by rapamycin, but not by the MEK inhibitor PD98059. Overexpression of a dominant negative Akt mutant or of the tumor suppressor phosphatase and tensin homologue, PTEN, in these cells also caused a significant reduction in MT1-MMP expression and invasion. The results demonstrate that IGF-IR controls tumor cell invasion by coordinately regulating MMP-2 expression and its MT1-MMP-mediated activation and identify PI 3-kinase/Akt/mTOR signaling as critical to this regulation.

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Acknowledgements

The authors are indebted to the following individuals for generous gifts: Dr David Kaplan for the Akt constructs, Dr Motohalu Seiki for the MT1-MMP promoter construct and Dr Nahum Sonenberg for the PTEN plasmid as well as for helpful discussions. We thank Mrs Lucia Fallavollita and Mr Tarek Boutros for excellent technical assistance and Drs Amir A Samani and Eric Chevet for helpful discussions. This study was supported by a grant from the Canadian Institute for Health Research to PB.

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  1. Department of Surgery, McGill University Health Center, The Royal Victoria Hospital, Montreal, Quebec, Canada

    Donglei Zhang & Pnina Brodt

  2. Department of Medicine, McGill University Health Center, The Royal Victoria Hospital, Montreal, Quebec, Canada

    Pnina Brodt

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  1. Donglei Zhang
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Correspondence to Pnina Brodt.

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Zhang, D., Brodt, P. Type 1 insulin-like growth factor regulates MT1-MMP synthesis and tumor invasion via PI 3-kinase/Akt signaling. Oncogene 22, 974–982 (2003). https://doi.org/10.1038/sj.onc.1206197

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