title: Overexpression and β-1,6-N-acetylglucosaminylation-initiated aberrant glycosylation of TIMP-1: a "double whammy" strategy in colon cancer progression.
abstract: There has been ongoing debate over whether tissue inhibitor of metalloproteinase-1 (TIMP-1) is pro- or anti-oncogenic. We confirmed that TIMP-1 reinforced cell proliferation in an αvβ3 integrin-dependent manner and conferred resistance against cytotoxicity triggered by TNF-α and IL-2 in WiDr colon cancer cells. The cell-proliferative effects of TIMP-1 contributed to clonogenicity and tumor growth during the onset and early phase of tumor formation in vivo and in vitro. However, mass-produced TIMP-1 impeded further tumor growth by tightly inhibiting the activities of collagenases, which are critical for tumor growth and malignant transformation. Tumor cells could overcome this impasse by overexpression of N-acetylglucosaminyltransferase V, which deteriorates TIMP-1 into an aberrant glycoform. The aberrant glycoform of TIMP-1 was responsible for the mitigated inhibition of collagenases. The outbalanced activities of collagenases can degrade the basement membrane and the interstitial matrix, which act as a physical barrier for tumor growth and progression more efficiently. The concomitant overexpression of TIMP-1 and N-acetylglucosaminyltransferase V enabled WiDr cells to show a higher tumor growth rate as well as more malignant behaviors in a three-dimensional culture system.
authors.affiliation: Cancer Biomarkers Development Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, South Korea.
authors.forename: Yong-Sam
authors.initials: YS
authors.lastname: Kim
authors.forename: Yeong Hee
authors.initials: YH
authors.lastname: Ahn
authors.forename: Kyoung Jin
authors.initials: KJ
authors.lastname: Song
authors.forename: Jeong Gu
authors.initials: JG
authors.lastname: Kang
authors.forename: Ju Hee
authors.initials: JH
authors.lastname: Lee
authors.forename: Seong Kook
authors.initials: SK
authors.lastname: Jeon
authors.forename: Hyoung-Chin
authors.initials: HC
authors.lastname: Kim
authors.forename: Jong Shin
authors.initials: JS
authors.lastname: Yoo
authors.forename: Jeong-Heon
authors.initials: JH
authors.lastname: Ko
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006031:Glycosylation; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000096:biosynthesis* / Q000235:genetics; D017351:N-Acetylglucosaminyltransferases / Q000096:biosynthesis* / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D039302:Integrin alphaVbeta3; D009363:Neoplasm Proteins; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D017351:N-Acetylglucosaminyltransferases; C052254:alpha-1,6-mannosylglycoprotein beta 1,6-N-acetylglucosaminyltransferase