Abstract
Cathepsin B is an endo-lysosomal cysteine protease. However, its increased expression and altered localization to the extracellular space, to mitochondria, or to the nucleus has been linked to tumor progression. In the present study, we show enhanced levels of cathepsin B in adenocarcinoma tissue in comparison to adjacent normal colon. Additionally, cathepsin B was observed in the nuclear compartment of mucosal cells in adenocarcinoma tissue samples and in the nuclei of the colorectal carcinoma cell line HCT116. Accordingly, a distinct 40-kDa form of cathepsin B was detected in HCT116 cells, which is proposed to represent a specific form lacking the signal peptide and parts of the propeptide. Trafficking studies with an EGFP-tagged N-terminally truncated form, mimicking the 40-kDa form, demonstrated accumulation in aggresome-like inclusion bodies, while EGFP-tagged full-length cathepsin B revealed regular sorting to endo-lysosomes. We conclude that the identity of nuclear cathepsin B in colorectal adenocarcinoma (in situ) and in carcinoma cells (in vitro) cannot be attributed to either full-length or 40-kDa N-terminally truncated cathepsin B forms. Hence, future studies are needed to demonstrate which form/s of cathepsin B may be sorted to the nuclei of colorectal carcinoma cells, and whether redundant regulation of related cathepsin expression occurs.
Highlights
Cysteine cathepsins play an important role in intra- and extra-cellular protein degradation and function as key enzymes in various physiological processes, which is true for the ubiquitously expressed endo- and exo-peptidase cathepsin B [1,2,3,4,5]
The human cathepsin B gene is comprised of 12 exons, and in tumor cells a number of different mRNA variants may be generated by alternative splicing [20]
The results indicate that the 40-kDa of cathepsin B detected in HCT116 cells is likely to be sorted to peri-nuclear aggresomes
Summary
Cysteine cathepsins play an important role in intra- and extra-cellular protein degradation and function as key enzymes in various physiological processes, which is true for the ubiquitously expressed endo- and exo-peptidase cathepsin B [1,2,3,4,5]. A splice variant has been detected that lacks exons 2 and 3, which encodes a protein lacking the 17 amino acid signal peptide and the first 34 amino acids of the propeptide This N-terminally truncated cathepsin B form is not sorted like the regular preproenzyme via the ER and the Golgi apparatus to endo-lysosome [21,22,23]. The N-terminally truncated specific form of cathepsin B was detected in the nucleus and may be imported into the mitochondrial matrix Such different and unusual sub-cellular locations of cysteine cathepsins have been reported in various types of cancer tissue such as breast carcinoma, colon carcinoma, thyroid carcinoma, and melanoma [5,8,9,21,24,25,26,27]. According to present information available, most of the N-terminally truncated forms of cysteine cathepsins are associated with pathological conditions, more with cancer [8,12,16,17,18,32,33,34]
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