Internalization and trafficking of CSPG-bound recombinant VAR2CSA lectins in cancer cells

Author:

Wang Chris Kedong,Nelepcu Irina,Hui Desmond,Oo Htoo Zarni,Truong Sarah,Zhao Sarah,Tahiry Zakir,Esfandnia Shaghayegh,Ghaidi Fariba,Adomat Hans,Dagil Robert,Gustavsson Tobias,Choudhary Swati,Salanti Ali,Sorensen Poul H.,Al Nakouzi Nader,Daugaard Mads

Abstract

AbstractProteoglycans are proteins that are modified with glycosaminoglycan chains. Chondroitin sulfate proteoglycans (CSPGs) are currently being exploited as targets for drug-delivery in various cancer indications, however basic knowledge on how CSPGs are internalized in tumor cells is lacking. In this study we took advantage of a recombinant CSPG-binding lectin VAR2CSA (rVAR2) to track internalization and cell fate of CSPGs in tumor cells. We found that rVAR2 is internalized into cancer cells via multiple internalization mechanisms after initial docking on cell surface CSPGs. Regardless of the internalization pathway used, CSPG-bound rVAR2 was trafficked to the early endosomes in an energy-dependent manner but not further transported to the lysosomal compartment. Instead, internalized CSPG-bound rVAR2 proteins were secreted with exosomes to the extracellular environment in a strictly chondroitin sulfate-dependent manner. In summary, our work describes the cell fate of rVAR2 proteins in tumor cells after initial binding to CSPGs, which can be further used to inform development of rVAR2-drug conjugates and other therapeutics targeting CSPGs.

Funder

St. Baldrick’s Foundation/American Association for Cancer Research/Stand Up to Cancer Pediatric Dream Team

Canadian Institutes of Health Research

NIH Prostate Cancer

The Novo Nordisk Foundation

Prostate Cancer Canada

MITACS

Publisher

Springer Science and Business Media LLC

Subject

Multidisciplinary

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