Translocating a high-affinity designer TIMP-1 to the cell membrane for total renal carcinoma inhibition: Putting the prion protein to good use

Bingjie Jiang, Yuewei Xu, Yihe Zhang, Meng Huee Lee*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

Membrane type 1-matrix metalloproteinase (MT1-MMP) and tumor necrosis factor α (TNF-α)-converting enzyme (TACE) are prominent membraneanchored metalloproteinases that regulate the turnover of extracellular matrix (ECM) components and bioactive molecules required for cancer proliferation. In this study, we describe a novel approach that would allow tissue inhibitor of metalloproteinase 1 (TIMP-1), the endogenous inhibitor of the matrix metalloproteinases (MMPs), to be translocated to the cell membrane for simultaneous MT1- MMP/TACE inhibition. We achieve this by fusing T1TACE, a designer TIMP-1 with superb affinities for MT1-MMP and TACE, to the glycosyl-phosphatidyl inositol anchor of prions to create a membrane-tethered, broad-spectrum inhibitor, named T1Pr αTACE, that colocalizes with MT1-MMP and TACE on the cell surface. Transduction of T1Pr αTACE in human fibrosarcoma cells results not only in a substantial reduction in gelatinolytic and TNF-α/heparin binding epithelial growth factor shedding activities but also in a loss of tubulogenic capability in threedimensional matrices. In renal carcinoma, T1Pr αTACE triggers cellular senescence and disrupts MMP-mediated proteolysis of ECM components such as fibronectin and collagen I, leading to an impairment in cell motility and survival under both in vitro and in vivo conditions. Taken together, our findings may provide a new perspective in TIMP targeting that could be exploited to halt metastatic renal carcinoma progression.

Original languageEnglish
Article numbere00128-19
JournalMolecular and Cellular Biology
Volume39
Issue number18
DOIs
Publication statusPublished - 1 Sept 2019

Keywords

  • ADAM
  • MMP
  • MT1-MMP
  • Prion
  • TACE
  • TIMP

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