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
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Han Ie Kim1,*, Hyun-Sung Lee2,*, Tae Hyun Kim1, Ju-Seog Lee3, Seung-Taek Lee4, Seo-Jin Lee1
1Department of Life Science & Biotechnology, Shingyeong University, Gyeonggi-do, 445-741, Republic of Korea
2Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, 77030, U.S.A
3Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, U.S.A
4Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 120-749, Republic of Korea
*These authors have contributed equally to this work
Seo-Jin Lee, e-mail: [email protected]
Keywords: TIMPs, tumorigenesis, c-Src, lung adenocarcinoma, PI3-kinase/AKT pathway
Received: April 03, 2015 Accepted: October 26, 2015 Published: November 07, 2015
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 α3β1, 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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