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 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.
authors.affiliation: Department of Life Science & Biotechnology, Shingyeong University, Gyeonggi-do, 445-741, Republic of Korea.
authors.forename: Han Ie
authors.initials: HIe
authors.lastname: Kim
authors.affiliation: Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, 77030, U.S.A.
authors.forename: Hyun-Sung
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Department of Life Science & Biotechnology, Shingyeong University, Gyeonggi-do, 445-741, Republic of Korea.
authors.forename: Tae Hyun
authors.initials: TH
authors.lastname: Kim
authors.affiliation: Department of Systems Biology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77054, U.S.A.
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 120-749, Republic of Korea.
authors.forename: Seung-Taek
authors.initials: ST
authors.lastname: Lee
authors.affiliation: Department of Life Science & Biotechnology, Shingyeong University, Gyeonggi-do, 445-741, Republic of Korea.
authors.forename: Seo-Jin
authors.initials: SJ
authors.lastname: Lee
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015153:Blotting, Western; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D055785:Gene Knockdown Techniques; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism*; D059467:Transcriptome; D014162:Transfection; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000081247:CSK Tyrosine-Protein Kinase; D051417:Focal Adhesion Kinase 1; D020782:Matrix Metalloproteinases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019716:Tissue Inhibitor of Metalloproteinase-2; D019061:src-Family Kinases; C560823:TIMP2 protein, human; C496050:PTK2 protein, human; C000631346:CSK protein, human
keywords: PI3-kinase/AKT pathway; TIMPs; c-Src; lung adenocarcinoma; tumorigenesis