Oncotarget

Research Papers:

Fungal lectin MpL enables entry of protein drugs into cancer cells and their subcellular targeting

Simon Žurga, Milica Perišić Nanut, Janko Kos _ and Jerica Sabotič

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Oncotarget. 2017; 8:26896-26910. https://doi.org/10.18632/oncotarget.15849

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Abstract

Simon Žurga1,*, Milica Perišić Nanut1,*, Janko Kos2, Jerica Sabotič1

1Department of Biotechnology, Jožef Stefan Institute, Ljubljana, Slovenia

2University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia

*These authors contributed equally to this work

Correspondence to:

Janko Kos, email: janko.kos@ffa.uni-lj.si

Keywords: lectin, drug delivery, cancer invasion, peptidase inhibitor, fusion proteins

Received: July 22, 2016     Accepted: February 20, 2017     Published: March 02, 2017

ABSTRACT

Lectins have been recognized as promising carrier molecules for targeted drug delivery. They specifically bind carbohydrate moieties on cell membranes and trigger cell internalization. Fungal lectin MpL (Macrolepiota procera lectin) does not provoke cancer cell cytotoxicity but is able to bind aminopeptidase N (CD13) and integrin α3β1, two glycoproteins that are overexpressed on the membrane of tumor cells. Upon binding, MpL is endocytosed in a clathrin-dependent manner and accumulates initially in the Golgi apparatus and, finally, in the lysosomes. For effective binding and internalization a functional binding site on the α-repeat is needed. To test the potential of MpL as a carrier for delivering protein drugs to cancer cells we constructed fusion proteins consisting of MpL and the cysteine peptidase inhibitors cystatin C and clitocypin. The fused proteins followed the same endocytic route as the unlinked MpL. Peptidase inhibitor-MpL fusions impaired both the intracellular degradation of extracellular matrix and the invasiveness of cancer cells. MpL is thus shown in vitro to be a lectin that can enable protein drugs to enter cancer cells, enhance their internalization and sort them to lysosomes and the Golgi apparatus.


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