Enhanced cathepsin L expression is mediated by different Ras effector pathways in fibroblasts and epithelial cells

Collette, John R.; Ülkü, Aylin S.; Der, Channing J.; Jones, A. K.; Erickson, Ann H.

doi:10.1002/ijc.20398

Cited by 39 publications

(20 citation statements)

References 62 publications

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“…As reported previously (36), the 35S effector loop mutant that activates the Raf-1-ERK pathway was sufficient to cause morphologic transformation comparable with that of v-H-ras and H-ras-V12, whereas 37G and 40C mutants had only a minimal transforming effect in NIH3T3 cells (data not shown). In concordance with the reported ability of the 35S mutant to induce cathepsin L expression in NIH3T3 cells (36), it was also the only mutant that enhanced the expression of cathepsin B and the total activity of cysteine cathepsins as well as reduced the levels of LAMP-1 and LAMP-2 ( Fig. 4A and B).…”

Section: Cancer Researchsupporting

confidence: 88%

Sensitization to the Lysosomal Cell Death Pathway by Oncogene-Induced Down-regulation of Lysosome-Associated Membrane Proteins 1 and 2

et al. 2008

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Section: Cancer Researchsupporting

confidence: 88%

Sensitization to the Lysosomal Cell Death Pathway by Oncogene-Induced Down-regulation of Lysosome-Associated Membrane Proteins 1 and 2

et al. 2008

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“…18,19). In particular, tumor promoters, such as phorbol ester, and certain oncogenes, such as ras, v-src, SV40 large T, and raf, were shown to induce cathepsin L expression and secretion (20)(21)(22)(23)(24)(25). Abundant literature has extended this observation to human tumors originating from various tissues.…”

Section: Introductionmentioning

confidence: 99%

Increased Expression and Activity of Nuclear Cathepsin L in Cancer Cells Suggests a Novel Mechanism of Cell Transformation

Goulet

Sansregret

Leduy

et al. 2007

Molecular Cancer Research

127

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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 phase. Here, we report that in many transformed cells the proteolytic processing of CDP/Cux is augmented and correlates with increased cysteine protease expression and activity in the nucleus. Taking advantage of an antibody that recognizes the prodomain of human cathepsin L, we showed that human cells express short cathepsin L species that do not contain a signal peptide, do not transit through the endoplasmic reticulum, are not glycosylated, and localize to the nucleus. We also showed that transformation by the ras oncogene causes rapid increases both in the production of short nuclear cathepsin L isoforms and in the processing of CDP/Cux. Using a cell-based assay, we showed that a cell-permeable inhibitor of cysteine proteases is able to delay the progression into S phase and the proliferation in soft agar of ras-transformed cells, whereas the non -cell-permeable inhibitor had no effect. Taken together, these results suggest that the role of cathepsin L in cancer might not be limited to its extracellular activities but may also involve its processing function in the nucleus. (Mol Cancer Res 2007;5(9):899 -907)

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“…Tumourassociated cysteine protease cathepsin L (CTSL) also has crucial roles at multiple stages of tumour progression and metastasis [9][10][11] . Cell lines transformed by certain oncogenes, including ras, are known to express high levels of CTSL [12][13][14] . 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 .…”

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confidence: 99%

Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease

et al. 2013

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Eradication of cancer cells while minimizing damage to healthy cells is a primary goal of cancer therapy. Highly selective drugs are urgently needed. Here we demonstrate a new prodrug strategy for selective cancer therapy that utilizes increased histone deacetylase (HDAC) and tumour-associated protease activities produced in malignant cancer cells. By coupling an acetylated lysine group to puromycin, a masked cytotoxic agent is created, which is serially activated by HDAC and an endogenous protease cathepsin L (CTSL) that remove the acetyl group first and then the unacetylated lysine group liberating puromycin. The agent selectively kills human cancer cell lines with high HDAC and CTSL activities. In vivo studies confirm tumour growth inhibition in prodrug-treated mice bearing human cancer xenografts. This cancer-selective cleavage of the masking group is a promising strategy for the next generation of anticancer drug development that could be applied to many other cytotoxic agents.

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Enhanced cathepsin L expression is mediated by different Ras effector pathways in fibroblasts and epithelial cells

Cited by 39 publications

References 62 publications

Sensitization to the Lysosomal Cell Death Pathway by Oncogene-Induced Down-regulation of Lysosome-Associated Membrane Proteins 1 and 2

Sensitization to the Lysosomal Cell Death Pathway by Oncogene-Induced Down-regulation of Lysosome-Associated Membrane Proteins 1 and 2

Increased Expression and Activity of Nuclear Cathepsin L in Cancer Cells Suggests a Novel Mechanism of Cell Transformation

Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease

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