Next Article in Journal
Carotenoid-Derived Flavor Precursors from Averrhoa carambola Fresh Fruit
Previous Article in Journal
Metabolomics Profiling Reveals Rehmanniae Radix Preparata Extract Protects against Glucocorticoid-Induced Osteoporosis Mainly via Intervening Steroid Hormone Biosynthesis
Article Menu
Issue 2 (January-2) cover image

Export Article

Open AccessArticle
Molecules 2019, 24(2), 255; https://doi.org/10.3390/molecules24020255

Targeting a Designer TIMP-1 to the Cell Surface for Effective MT1-MMP Inhibition: A Potential Role for the Prion Protein in Renal Carcinoma Therapy

Department of Biological Sciences, Xian Jiaotong Liverpool University, 111 Ren Ai Road, Suzhou 215123, China
*
Author to whom correspondence should be addressed.
Received: 10 December 2018 / Revised: 3 January 2019 / Accepted: 7 January 2019 / Published: 11 January 2019
Full-Text   |   PDF [8251 KB, uploaded 11 January 2019]   |  

Abstract

Renal carcinoma cells express Membrane Type 1-Matrix Metalloproteinase (MT1-MMP, MMP-14) to degrade extracellular matrix components and a range of bioactive molecules to allow metastasis and cell proliferation. The activity of MT1-MMP is modulated by the endogenous inhibitors, Tissue Inhibitor of Metalloproteinases (TIMPs). In this study, we describe a novel strategy that would enable a “designer” TIMP-1 tailored specifically for MT1-MMP inhibition (V4A/P6V/T98L; Kiapp 1.66 nM) to be targeted to the plasma membrane for more effective MT1-MMP inhibition. To achieve this, we fuse the designer TIMP-1 to the glycosyl-phosphatidyl inositol (GPI) anchor of the prion protein to create a membrane-tethered, high-affinity TIMP variant named “T1Pr αMT1” that is predominantly located on the cell surface and co-localised with MT1-MMP. Confocal microscopy shows that T1Pr αMT1 is found throughout the cell surface in particular the membrane ruffles where MT1-MMP is most abundant. Expression of T1Pr αMT1 brings about a complete abrogation of the gelatinolytic activity of cellular MT1-MMP in HT1080 fibrosarcoma cells whilst in renal carcinoma cells CaKi-1, the GPI-TIMP causes a disruption in MMP-mediated proteolysis of ECM components such as fibronectin, collagen I and laminin that consequently triggers a downstream senescence response. Moreover, the transduced cells also suffer from an impairment in proliferation and survival in vitro as well as in NOD/SCID mouse xenograft. Taken together, our findings demonstrate that the GPI anchor of prion could be exploited as a targeting device in TIMP engineering for MT1-MMP inhibition with a potential in renal carcinoma therapy. View Full-Text
Keywords: MT1-MMP; TIMP; renal carcinoma; cancer therapy; prion; GPI anchor; protein engineering MT1-MMP; TIMP; renal carcinoma; cancer therapy; prion; GPI anchor; protein engineering
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
SciFeed

Share & Cite This Article

MDPI and ACS Style

Jiang, B.; Liu, J.; Lee, M.H. Targeting a Designer TIMP-1 to the Cell Surface for Effective MT1-MMP Inhibition: A Potential Role for the Prion Protein in Renal Carcinoma Therapy. Molecules 2019, 24, 255.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top