Growth-stimulatory activity of TIMP-2 is mediated through c-Src activation followed by activation of FAK, PI3-kinase/AKT, and ERK1/2 independent of MMP inhibition in lung adenocarcinoma cells

Han Ie Kim, Hyun Sung Lee, Tae Hyun Kim, Ju Seog Lee, Seung Taek Lee, Seo Jin Lee

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Tissue inhibitors of metalloproteinases (TIMPs) control extracellular matrix (ECM) homeostasis by inhibiting the activity of matrix metalloproteinases (MMPs), which are associated with ECM turnover. Recent studies have revealed that TIMPs are implicated in tumorigenesis in both MMP-dependent and MMP-independent manners. We examined a mechanism by which TIMP-2 stimulated lung adenocarcinoma cell proliferation, independent of MMP inhibition. The stimulation of growth by TIMP-2 in A549 cells required c-Src kinase activation. c-Src kinase activity, induced by TIMP-2, concomitantly increased FAK, phosphoinositide 3-kinase (PI3-kinase)/AKT, and ERK1/2 activation. Selective knockdown of integrin a3β1, known as a TIMP-2 receptor, did not significantly change TIMP-2 growth promoting activity. Furthermore, we showed that high TIMP-2 expression in lung adenocarcinomas is associated with a worse prognosis from multiple cohorts, especially for stage I lung adenocarcinoma. Through integrated analysis of The Cancer Genome Atlas data, TIMP-2 expression was significantly associated with the alteration of driving genes, c-Src activation, and PI3-kinase/AKT pathway activation. Taken together, our results demonstrate that TIMP-2 stimulates lung adenocarcinoma cell proliferation through c-Src, FAK, PI3-kinase/AKT, and ERK1/2 pathway activation in an MMP-independent manner.

Original languageEnglish
Pages (from-to)42905-42922
Number of pages18
JournalOncotarget
Volume6
Issue number40
DOIs
Publication statusPublished - 2015 Jan 1

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Tissue Inhibitor of Metalloproteinase-2
1-Phosphatidylinositol 4-Kinase
Matrix Metalloproteinase 2
Matrix Metalloproteinases
Growth
Tissue Inhibitor of Metalloproteinases
Extracellular Matrix
Cell Proliferation
src Genes
Growth Inhibitors
Adenocarcinoma of lung
MAP Kinase Signaling System
Atlases
Integrins
Carcinogenesis
Homeostasis
Genome

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

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title = "Growth-stimulatory activity of TIMP-2 is mediated through c-Src activation followed by activation of FAK, PI3-kinase/AKT, and ERK1/2 independent of MMP inhibition in lung adenocarcinoma cells",
abstract = "Tissue inhibitors of metalloproteinases (TIMPs) control extracellular matrix (ECM) homeostasis by inhibiting the activity of matrix metalloproteinases (MMPs), which are associated with ECM turnover. Recent studies have revealed that TIMPs are implicated in tumorigenesis in both MMP-dependent and MMP-independent manners. We examined a mechanism by which TIMP-2 stimulated lung adenocarcinoma cell proliferation, independent of MMP inhibition. The stimulation of growth by TIMP-2 in A549 cells required c-Src kinase activation. c-Src kinase activity, induced by TIMP-2, concomitantly increased FAK, phosphoinositide 3-kinase (PI3-kinase)/AKT, and ERK1/2 activation. Selective knockdown of integrin a3β1, known as a TIMP-2 receptor, did not significantly change TIMP-2 growth promoting activity. Furthermore, we showed that high TIMP-2 expression in lung adenocarcinomas is associated with a worse prognosis from multiple cohorts, especially for stage I lung adenocarcinoma. Through integrated analysis of The Cancer Genome Atlas data, TIMP-2 expression was significantly associated with the alteration of driving genes, c-Src activation, and PI3-kinase/AKT pathway activation. Taken together, our results demonstrate that TIMP-2 stimulates lung adenocarcinoma cell proliferation through c-Src, FAK, PI3-kinase/AKT, and ERK1/2 pathway activation in an MMP-independent manner.",
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Growth-stimulatory activity of TIMP-2 is mediated through c-Src activation followed by activation of FAK, PI3-kinase/AKT, and ERK1/2 independent of MMP inhibition in lung adenocarcinoma cells. / Kim, Han Ie; Lee, Hyun Sung; Kim, Tae Hyun; Lee, Ju Seog; Lee, Seung Taek; Lee, Seo Jin.

In: Oncotarget, Vol. 6, No. 40, 01.01.2015, p. 42905-42922.

Research output: Contribution to journalArticle

TY - JOUR

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AU - Kim, Han Ie

AU - Lee, Hyun Sung

AU - Kim, Tae Hyun

AU - Lee, Ju Seog

AU - Lee, Seung Taek

AU - Lee, Seo Jin

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