Nuclear Legumain Activity in Colorectal Cancer
Open Access
- 10 January 2013
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 8 (1), e52980
- https://doi.org/10.1371/journal.pone.0052980
Abstract
The cysteine protease legumain is involved in several biological and pathological processes, and the protease has been found over-expressed and associated with an invasive and metastatic phenotype in a number of solid tumors. Consequently, legumain has been proposed as a prognostic marker for certain cancers, and a potential therapeutic target. Nevertheless, details on how legumain advances malignant progression along with regulation of its proteolytic activity are unclear. In the present work, legumain expression was examined in colorectal cancer cell lines. Substantial differences in amounts of pro- and active legumain forms, along with distinct intracellular distribution patterns, were observed in HCT116 and SW620 cells and corresponding subcutaneous xenografts. Legumain is thought to be located and processed towards its active form primarily in the endo-lysosomes; however, the subcellular distribution remains largely unexplored. By analyzing subcellular fractions, a proteolytically active form of legumain was found in the nucleus of both cell lines, in addition to the canonical endo-lysosomal residency. In situ analyses of legumain expression and activity confirmed the endo-lysosomal and nuclear localizations in cultured cells and, importantly, also in sections from xenografts and biopsies from colorectal cancer patients. In the HCT116 and SW620 cell lines nuclear legumain was found to make up approximately 13% and 17% of the total legumain, respectively. In similarity with previous studies on nuclear variants of related cysteine proteases, legumain was shown to process histone H3.1. The discovery of nuclear localized legumain launches an entirely novel arena of legumain biology and functions in cancer.Keywords
This publication has 64 references indexed in Scilit:
- Targeting Cell Surface Alpha(v)beta(3) Integrin Increases Therapeutic Efficacies of a Legumain Protease-Activated Auristatin ProdrugMolecular Pharmaceutics, 2011
- Nucleoplasmic calcium regulates cell proliferation through legumainJournal of Hepatology, 2011
- Blastocystis Legumain Is Localized on the Cell Surface, and Specific Inhibition of Its Activity Implicates a Pro-survival Role for the EnzymePublished by Elsevier BV ,2010
- Critical Role for Asparagine Endopeptidase in Endocytic Toll-like Receptor Signaling in Dendritic CellsImmunity, 2009
- Systematic identification of cell cycle-dependent yeast nucleocytoplasmic shuttling proteins by prediction of composite motifsProceedings of the National Academy of Sciences of the United States of America, 2009
- A dyad of lymphoblastic lysosomal cysteine proteases degrades the antileukemic drug l-asparaginaseJCI Insight, 2009
- Mice lacking asparaginyl endopeptidase develop disorders resembling hemophagocytic syndromeProceedings of the National Academy of Sciences of the United States of America, 2009
- Cathepsin L Proteolytically Processes Histone H3 During Mouse Embryonic Stem Cell DifferentiationCell, 2008
- Neuroprotective Actions of PIKE-L by Inhibition of SET Proteolytic Degradation by Asparagine EndopeptidaseMolecular Cell, 2008
- A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye bindingAnalytical Biochemistry, 1976