Up‐regulation of cathepsin X in <i>Helicobacter pylori</i> gastritis and gastric cancer

Krueger, Sabine; Kalinski, Thomas; Hundertmark, Tanja; Wex, Thomas; Küster, Denise; Peitz, Ulrich; Ebert, Matthias P.; Nägler, Dorit K.; Kellner, Udo; Malfertheiner, Peter; Naumann, Michael; Röcken, Christoph; Roessner, Albert

doi:10.1002/path.1820

Cited by 85 publications

(71 citation statements)

References 33 publications

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“…Indeed, the inhibition of cathepsin X activity with anti-catalytic antibodies did not result in impaired migration of breast cancer cells (19). Yet, as we have recently shown, inhibition of cathepsin X at the mRNA level leads to decreased migration of gastric epithelial cancer cells (18). This apparent contradiction led us to speculate that the enzyme may be involved in mechanisms of adhesion, migration, or invasion, which are not related to proteolysis.…”

mentioning

confidence: 75%

“…In this context, using specific silencing of gene expression, we have shown recently that transmigration of human gastric epithelial tumor cells (AGS) through ECM can indeed be reduced if the cells are transfected with cathepsin X antisense oligonucleotides (18). Similarly, transmigration of HUVECs through human ECM is also reduced after transfection with small interfering RNAs targeted against cathepsin X (data not shown).…”

Section: Discussionmentioning

confidence: 98%

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RGD-dependent Binding of Procathepsin X to Integrin αvβ3 Mediates Cell-adhesive Properties

Lechner

Assfalg-Machleidt

Zahler

et al. 2006

Journal of Biological Chemistry

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Secreted lysosomal cysteine proteases (cathepsins) are involved in degradation and remodeling of the extracellular matrix, thus contributing to cell adhesion and migration. Among the eleven human lysosomal cysteine proteases, only procathepsin X contains an RGD motif located in a highly exposed region of the propeptide, which may allow binding of the proenzyme to RGD-recognizing integrins. Here, we have tested procathepsin X for cell-adhesive properties and found that it supports integrin ␣ v ␤ 3 -dependent attachment and spreading of human umbilical vein endothelial cells. Using sitedirected mutants of procathepsin X, we proved that this effect is mediated by the RGD sequence within the proregion of the protease. Endogenous procathepsin X is transported to the plasma membrane, accumulates in vesicles at lamellipodia of the human umbilical vein endothelial cell, and is partly associated with the cell surface, as shown by immunofluorescence. In addition, procathepsin X is partly co-localized with integrin ␤ 3 , as detected by immunogold electron microscopy. A direct interaction between endogenous procathepsin X and ␣ v ␤ 3 was demonstrated by co-immunoprecipitation. Moreover, surface plasmon resonance analysis revealed significant and RGD-dependent binding of procathepsin X to integrin ␣ v ␤ 3 . Our results provide for the first time evidence that the extracellular function of cathepsin X may include binding to integrins thereby modulating the attachment of migrating cells to ECM components. Cellular migration through extracellular matrix (ECM)2 requires both cell adhesion to and proteolysis of ECM components. A large number of proteases, including matrix metalloproteases, serine proteases, but also lysosomal cysteine proteases are known to be responsible for ECM breakdown, particularly during tumor invasion (1-3). Cell adhesion to ECM on the other hand is largely mediated by heterodimeric cell surface receptors of the integrin family. Integrins are composed of noncovalently associated ␣ and ␤ chains that form various heterodimers with distinct adhesive specificities (4, 5).Several proteases have been shown to mediate adhesion and migration of cells through interaction with integrins. Thus, prothrombin, the zymogen of a multifunctional serine protease of the blood coagulation system, interacts directly with integrins via its RGD sequence, a motif involved in integrin binding (6 -8). Although the RGD sequence is partly buried in the native conformation (9), prothrombin can bind in an RGD-dependent fashion to integrins ␣ IIb ␤ 3 of platelets and ␣ v ␤ 3 of cultured human endothelial cells (10 -12). There is increasing evidence that interactions between prothrombin and ␤ 3 integrins play important roles in the regulation of hemostatic and vascular functions. Furthermore, the urokinase-type plasminogen activator/urokinase receptor (uPA/ uPAR) system not only plays a key role in fibrinolysis but also regulates cell adhesion, cell migration, and cell proliferation through interaction with integrins (for review, see Ref...

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mentioning

confidence: 75%

Section: Discussionmentioning

confidence: 98%

RGD-dependent Binding of Procathepsin X to Integrin αvβ3 Mediates Cell-adhesive Properties

Lechner

Assfalg-Machleidt

Zahler

et al. 2006

Journal of Biological Chemistry

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“…Increased levels of Ctsz have been reported in several cancers, however, including gastric and breast cancers (40,41). In addition, our previous work suggested that Ctsz (then called cathepsin X) compensates for the loss of Ctsb in primary cancer cells (20).…”

Section: Discussionmentioning

confidence: 99%

Synergistic antitumor effects of combined cathepsin B and cathepsin Z deficiencies on breast cancer progression and metastasis in mice

Sevenich

Schurigt

Sachse

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

148

119

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The lysosomal cysteine proteases cathepsin B (Ctsb) and cathepsin Z (Ctsz, also called cathepsin X/P) have been implicated in cancer pathogenesis. Compensation of Ctsb by Ctsz in Ctsb −/− mice has been suggested. To further define the functional interplay of these proteases in the context of cancer, we generated Ctsz null mice, crossed them with Ctsb-deficient mice harboring a transgene for the mammary duct–specific expression of polyoma middle T oncogene (PymT), and analyzed the effects of single and combined Ctsb and Ctsz deficiencies on breast cancer progression. Single Ctsb deficiency resulted in delayed detection of first tumors and reduced tumor burden, whereas Ctsz-deficient mice had only a prolonged tumor-free period. However, only a trend toward reduced metastatic burden without statistical significance was detected in both single mutants. Strikingly, combined loss of Ctsb and Ctsz led to additive effects, resulting in significant and prominent delay of early and advanced tumor development, improved histopathologic tumor grading, as well as a 70% reduction in the number of lung metastases and an 80% reduction in the size of these metastases. We conclude that the double deficiency of Ctsb and Ctsz exerts significant synergistic anticancer effects, whereas the single deficiencies demonstrate at least partial reciprocal compensation.

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“…With regard to the role of cathepsin X in invasive processes, transwell (Boyden chamber) assays had previously revealed a decreased invasive potential of tumor cells lacking cathepsin X (Krueger et al , 2005 ). Similarly, cathepsin X-deficient PC-3 cells display a reduction of the invasive capacity in transmigration assays (data not shown).…”

Section: Bereitgestellt Von | Universitaetsbibliothek Der Lmu Muenchenmentioning

confidence: 99%

“…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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confidence: 99%

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 Helicobacter pylori gastritis and gastric cancer

Cited by 85 publications

References 33 publications

RGD-dependent Binding of Procathepsin X to Integrin αvβ3 Mediates Cell-adhesive Properties

RGD-dependent Binding of Procathepsin X to Integrin αvβ3 Mediates Cell-adhesive Properties

Synergistic antitumor effects of combined cathepsin B and cathepsin Z deficiencies on breast cancer progression and metastasis in mice

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

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