Overexpression and β-1,6-N-Acetylglucosaminylation-initiated Aberrant Glycosylation of TIMP-1

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. Background: Early TIMP-1 accumulation may impede cancer progression, and cancer cells need to reduce the antiproteolytic burden. Results: Early overexpression and later aberrant glycosylation of TIMP-1 support tumor progression. Conclusion: Concomitant overexpression of TIMP-1 and GnT-V directs accelerated tumor growth and cancer progression in vivo and in vitro. Significance: An answer to the debate on whether TIMP-1 is pro- or anti-oncogenic is given.