2007
DOI: 10.1158/1541-7786.mcr-07-0160
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Increased Expression and Activity of Nuclear Cathepsin L in Cancer Cells Suggests a Novel Mechanism of Cell Transformation

Abstract: It is generally accepted that the role of cathepsin L in cancer involves its activities outside the cells once it has been secreted. However, cathepsin L isoforms that are devoid of a signal peptide were recently shown to be present in the nucleus where they proteolytically process the CCAAT-displacement protein/cut homeobox (CDP/Cux) transcription factor. A role for nuclear cathepsin L in cell proliferation could be inferred from the observation that the CDP/Cux processed isoform can accelerate entry into S p… Show more

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Cited by 127 publications
(105 citation statements)
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“…Thus, the upregulation of CTSL is recognized as a hallmark of metastatic cancers and could be utilized as a prognostic marker 9,10,11,15,16 . Recently, nuclear-localized CTSL involved in cancer has been revealed, suggesting that CTSL may have key roles in the nucleus beyond its known lysosomal and extracellular activities 11,[16][17][18][19] . Although the therapeutic potential of CTSL inhibitors has not been fully characterized in preclinical studies, targeting CTSL activity is considered as a strategy for anticancer therapy 20 .…”
mentioning
confidence: 99%
“…Thus, the upregulation of CTSL is recognized as a hallmark of metastatic cancers and could be utilized as a prognostic marker 9,10,11,15,16 . Recently, nuclear-localized CTSL involved in cancer has been revealed, suggesting that CTSL may have key roles in the nucleus beyond its known lysosomal and extracellular activities 11,[16][17][18][19] . Although the therapeutic potential of CTSL inhibitors has not been fully characterized in preclinical studies, targeting CTSL activity is considered as a strategy for anticancer therapy 20 .…”
mentioning
confidence: 99%
“…Accumulating evidence now points to a crucial role of the shorter CUX1 isoforms in hyperproliferation and tumorigenesis. Proteolytic processing of CUX1 was found to be enhanced in many cancer cell lines (50), and constitutive expression of p110-CUX1 was shown to stimulate cell proliferation by accelerating S phase entry (51). Aberrant expression of p75-CUX1 mRNA or protein was observed in several breast cancer cell lines (38) and a significant association was established between higher p75-CUX1 expression and a diffuse infiltrative growth pattern in invasive tumors (38).…”
mentioning
confidence: 99%
“…In contrast, the fulllength protein did not have any effect in the same assays. 5 Whereas proteolytic processing of CUX1 was shown to be tightly regulated during cell cycle progression in normal cells, increased processing of CUX1 was reported both in primary human uterine leiomyomas and several cancer cell lines (23,24). In transgenic mice, forced expression of short CUX1 proteins enhanced the susceptibility to various malignancies, in particular in the myeloid cell lineage (25).…”
Section: Mol Cancer Res 2008;6(4) April 2008mentioning
confidence: 99%
“…In uterine leiomyomas, p110 CUX1 was frequently expressed at a higher level in the tumor than in the adjacent myometrium (23). In many cancer cell lines, increased expression and activity of nuclear cathepsin L was found to result in a higher ratio of processed over the full-length CUX1 protein (24). Interestingly, the intron 20 -mRNA and p75 isoforms were found to be expressed only weakly or not at all in primary human mammary epithelial cells and normal breast tissues, but were detected in many breast tumor cell lines and human breast tumors (13).…”
Section: Introductionmentioning
confidence: 99%