Overexpression and β-1,6-N-Acetylglucosaminylation-initiated aberrant glycosylation of TIMP-1: A "double whammy" strategy in colon cancer progression

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Title
Overexpression and β-1,6-N-Acetylglucosaminylation-initiated aberrant glycosylation of TIMP-1: A "double whammy" strategy in colon cancer progression
Author(s)
Yong Sam Kim; Y H Ahn; Kyoung Jin Song; Jeong Gu Kang; Ju Hee Song; S K Jeon; Hyoung-Chin Kim; J S Yoo; Jeong Heon Ko
Bibliographic Citation
Journal of Biological Chemistry, vol. 287, no. 39, pp. 32467-32478
Publication Year
2012
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.
ISSN
0021-9258
Publisher
Amer Soc Biochemistry Molecular Biology Inc
DOI
http://dx.doi.org/10.1074/jbc.M112.370064
Type
Article
Appears in Collections:
Synthetic Biology and Bioengineering Research Institute > Genome Editing Research Center > 1. Journal Articles
Ochang Branch Institute > Division of Bioinfrastructure > Laboratory Animal Resource Center > 1. Journal Articles
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