Up‐regulation of cathepsin X in prostate cancer and prostatic intraepithelial neoplasia

Nägler, Dorit K.; Krüger, Sabine; Kellner, Angela; Ziomek, Edmund; Ménard, Robert; Buhtz, Peter; Krams, Matthias; Roessner, Albert; Kellner, Udo

doi:10.1002/pros.20046

Cited by 73 publications

(44 citation statements)

References 37 publications

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“…High CtsZ expression correlates with advanced malignancy in hepatocellular carcinomas and colorectal and prostate cancer (Hidaka et al 2000;Nagler et al 2004;Wang et al 2011;Vizin et al 2012). Interestingly, CtsZ is also up-regulated in the inflammatory condition of Helicobacter pyloriassociated gastritis, further increased in gastric cancer, and induced in both infiltrating macrophages and epithelial cells (Krueger et al 2005;Bernhardt et al 2010).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, compared with other cathepsins, relatively little is known about the roles of CtsZ in cancer. Analysis of patient samples has revealed a correlation between high CtsZ expression levels and advanced malignancy in hepatocellular carcinomas and colorectal, gastric, and prostate cancer (Hidaka et al 2000;Nagler et al 2004;Krueger et al 2005;Wang et al 2011;Vizin et al 2012), suggesting potential cancer-promoting functions in different tumor microenvironments.To investigate the relative roles of CtsZ in TAMs and cancer cells in vivo, we used the RIP1-Tag2 (RT2) PanNET model, in which the SV40 T antigen (Tag) viral oncogene is specifically expressed in b cells of the pancreatic islets under the control of the rat insulin promoter (RIP) (Hanahan 1985). SV40 Tag expression inactivates p53 and pRb, resulting in the development of PanNETs through a stereotypical progression from hyperplastic islets to angiogenic islets and finally multiple end-stage tumors.…”

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Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix

et al. 2014

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During the process of tumor progression, cancer cells can produce the requisite growth-and invasion-promoting factors and can also rely on noncancerous cells in the tumor microenvironment as an alternative, cell-extrinsic source. However, whether the cellular source influences the function of such tumor-promoting factors remains an open question. Here, we examined the roles of the cathepsin Z (CtsZ) protease, which is provided by both cancer cells and macrophages in pancreatic neuroendocrine tumors in humans and mice. We found that tumor proliferation was exclusively regulated by cancer cell-intrinsic functions of CtsZ, whereas tumor invasion required contributions from both macrophages and cancer cells. Interestingly, several of the tumor-promoting functions of CtsZ were not dependent on its described catalytic activity but instead were mediated via the Arg-Gly-Asp (RGD) motif in the enzyme prodomain, which regulated interactions with integrins and the extracellular matrix. Together, these results underscore the complexity of interactions within the tumor microenvironment and indicate that cellular source can indeed impact molecular function.[Keywords: cell invasion; cell migration; tumor microenvironment; protease] Supplemental material is available for this article. Received July 26, 2014; revised version accepted August 29, 2014. Tumors arise in complex tissue microenvironments in which a multitude of different noncancerous cell types can potently regulate disease initiation and progression (Hanahan and Coussens 2012;Quail and Joyce 2013). In addition, interactions with the extracellular matrix (ECM) are critical for modulating cell behavior, including enhancing cell survival and promoting invasion via ECM turnover and proteolysis (Lu et al. 2012;Sevenich and Joyce 2014). The ECM is a heterogeneous mix of proteins and polysaccharides, including different collagens, laminins, fibronectin, and heparan sulfate proteoglycans, which form an intricate network that confers tissue structure and regulates growth factor availability (Hynes and Naba 2012;Lu et al. 2012). Integrins are central in mediating interactions between cells and the surrounding ECM, and integrin engagement at the cell surface results in activation of downstream signaling nodes, including focal adhesion kinase (FAK) and Src kinase, to promote cancer cell proliferation, survival, migration, and invasion (Desgrosellier and Cheresh 2010;Huttenlocher and Horwitz 2011;Moreno-Layseca and Streuli 2014).Among the noncancerous cell types that modulate tumorigenesis, tumor-associated macrophages (TAMs) have emerged as critical regulators of tumor progression (Biswas et al. 2013;Noy and Pollard 2014). This is particularly evident in tumor invasion, as TAMs provide a major source of proteases that modulate the ECM (Joyce and Pollard 2009). In determining the mechanisms by which TAMs promote different tumorigenic processes, the focus to date has been predominantly centered on identifying factors that are TAM-specific or TAM-enriched, which are not necessa...

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Section: Discussionmentioning

confidence: 99%

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Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix

et al. 2014

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“…of triplicate wells. carcinomas, and related to the invasiveness of tumour cells (Kruger et al, 2005;Nagler et al, 2004). However, it has been demonstrated that it does not contribute to ECM degradation or affect ECM-dependent cell migration (Kos et al, 2005;Lechner et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

The role of cathepsin X in the migration and invasiveness of T lymphocytes

Jevnikar

Obermajer

Bogyo

et al. 2008

Journal of Cell Science

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Cathepsin X is a lysosomal cysteine protease exhibiting carboxypeptidase activity. Its expression is high in the cells of immune system and its function has been related to the processes of inflammatory and immune responses. It regulates processes such as adhesion, T lymphocyte activation and phagocytosis through its interaction with β2 integrins. To investigate the role of cathepsin X in the migration of T lymphocytes, Jurkat T lymphocytes were stably transfected with a pcDNA3 expression vector containing cathepsin X cDNA. The cathepsin-X-overexpressing T lymphocytes exhibited polarised migration-associated morphology, enhanced migration on 2D and 3D models using intercellular adhesion molecule 1 (ICAM1)- and Matrigel-coated surfaces, and increased homotypic aggregation. The increased invasiveness of cathepsin-X-overexpressing cells does not involve proteolytic degradation of extracellular matrix. Confocal microscopy showed that the active mature form of cathepsin X was colocalised in migrating cells together with lymphocyte-function-associated antigen 1 (LFA-1). The colocalisation was particularly evident at the trailing edge protrusion, the uropod, that has an important role in T lymphocyte migration and cell-cell interactions. We propose that cathepsin X causes cytoskeletal rearrangements and stimulates migration of T lymphocytes by modulating the activity of the β2 integrin receptor LFA-1.

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“…Hence, cancer cells have adopted several ways to overcome this powerful tumor suppressor pathway. Besides mutations in senescence-relevant genes such as p53 , one such mechanism seems to act through lysosomal cathepsins such as cathepsin X, which is upregulated in several cancers ( N ä gler et al, 2004 ;Krueger et al , 2005 ) and has been shown to participate in invasive processes (Sevenich et al , 2010 ). Remarkably, the downregulation of cathepsin X leads to accelerated cellular senescence (Kraus et al , 2011 ).…”

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IGF-I receptor phosphorylation is impaired in cathepsin X-deficient prostate cancer cells

Kraus¹,

Fruth

Bunsen

et al. 2012

Biological Chemistry

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Abstract:The cysteine-type peptidase cathepsin X is highly upregulated in several cancers and presumably promotes tumor invasion through bypassing cellular senescence. Here, we present first evidence that the underlying mechanism may involve the regulation of the insulin-like growth factor (IGF) system, a well-known activator of proliferating tumor cells. Cathepsin X deficiency leads to a reduced phosphorylation of the IGF-I receptor in response to IGF-I stimulation. In addition, downstream signaling through focal adhesion kinase was also affected. Taken together, our results indicate that cathepsin X is able to assist in IGF signaling, which may be an important progress toward understanding cathepsin X-dependent tumorigenesis.

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Up‐regulation of cathepsin X in prostate cancer and prostatic intraepithelial neoplasia

Cited by 73 publications

References 37 publications

Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix

Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix

The role of cathepsin X in the migration and invasiveness of T lymphocytes

IGF-I receptor phosphorylation is impaired in cathepsin X-deficient prostate cancer cells

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