Lysosomal cysteine protease cathepsin S is involved in cancer cell motility by regulating store-operated Ca2+ entry

Lin, Hsiao Han; Chen, Szu Jung; Shen, Meng‐Ru; Huang, Yi-Chung; Hsieh, Hsing Pang; Lin, Shu Yu; Lin, Chun Cheng; Chang, Wun Shaing Wayne; Chang, Jang Yang

doi:10.1016/j.bbamcr.2019.07.012

Cited by 18 publications

(18 citation statements)

References 46 publications

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“…Furthermore, other studies also demonstrated that inhibition of CTSS could trigger abnormality of tumor metabolism and subsequent apoptosis, which was highly related to its essential role in lysosome [17,18]. Besides, inhibition of CTSS reduced cancer cell invasion [19,20]. This phenomenon was observed in several studies and the reason might attribute to its role in ECM degradation [9], but the underlying mechanism was still vague.…”

Section: Discussionmentioning

confidence: 94%

Inhibition of Cathepsin S Restores TGF-β-induced Epithelial-to-mesenchymal Transition and Tight Junction Turnover in Glioblastoma Cells

Li¹,

Shao²,

Peng³

et al. 2021

J. Cancer

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Background: Invasive growth is one of the most typical features of aggressive types of malignant cancer, including glioblastoma. Lysosomal cysteine protease-cathepsin S (CTSS), has been reported to be involved in invasive growth and distant metastasis of cancer cells. However, the underlying mechanisms remained elusive. Methods: U87 and U251 human glioblastoma cell lines were applied in this study. Cell migration and invasion ability were measured by wound healing assay and transwell assay. Western blot was employed to detect the expression levels of proteins. Immunofluorescence assays of cells and tissues were used to visualize the localization and expression of proteins. The SPSS software was used for statistical analysis. Results: Our results showed that the high expression of CTSS was link with the grades of glioma tissues. The CTSS inhibitor-Z-FL-COCHO (ZFL), could attenuate TGF-β-induced invasive growth as proven by wound healing and transwell assays. Furthermore, inhibition of CTSS could reverse TGF-β-induced epithelial-to-mesenchymal transition (EMT) and restore TGF-β-triggered tight junction proteins turnover, thus decreasing glioblastoma cell mobility. We also observed that TGF-β could change the morphology of glioblastoma cells, redistribute intermediate-filament, vimentin, which was highly relevant to mesenchymal type cells and enhanced mobility. However, inhibition of CTSS could significantly restore this transformation. Our results proved that PI3K/AKT/mTOR pathway was significantly suppressed in the TGF-β+ZFL (CTSS inhibitor) groups, and AKT activator-SC79, could reverse the anti-invasion effect of CTSS, indicating an important role of PI3K/AKT/mTOR pathway in this process. Conclusion: Z-FL-COCHO (ZFL), a CTSS inhibitor, could reverse TGF-β-induced EMT and change of tight junction proteins via PI3K/AKT/mTOR pathway.

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Section: Discussionmentioning

confidence: 94%

Inhibition of Cathepsin S Restores TGF-β-induced Epithelial-to-mesenchymal Transition and Tight Junction Turnover in Glioblastoma Cells

Li¹,

Shao²,

Peng³

et al. 2021

J. Cancer

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“…Interestingly, CTSS has also been linked to breast-to-brain metastasis via processing of the junctional adhesion molecule-B and subsequent blood-brain barrier transmigration [75]. Recently, CTSS was shown to play an important role in mediating Ca 2+ homeostasis by regulating stromal interaction molecule (STIM) 1 trafficking, and inhibition of CTSS resulted in decreased cell migration and invasion [133]. In addition, CTSS promoted pericellular hydrolysis of the ECM within the tumor microenvironment, facilitating endothelial invasion [76].…”

Section: Lung Cancermentioning

confidence: 99%

Cathepsin S: investigating an old player in lung disease pathogenesis, comorbidities, and potential therapeutics

et al. 2020

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Dysregulated expression and activity of cathepsin S (CTSS), a lysosomal protease and a member of the cysteine cathepsin protease family, is linked to the pathogenesis of multiple diseases, including a number of conditions affecting the lungs. Extracellular CTSS has potent elastase activity and by processing cytokines and host defense proteins, it also plays a role in the regulation of inflammation. CTSS has also been linked to G-coupled protein receptor activation and possesses an important intracellular role in major histocompatibility complex class II antigen presentation. Modulated CTSS activity is also associated with pulmonary disease comorbidities, such as cancer, cardiovascular disease, and diabetes. CTSS is expressed in a wide variety of immune cells and is biologically active at neutral pH. Herein, we review the significance of CTSS signaling in pulmonary diseases and associated comorbidities. We also discuss CTSS as a plausible therapeutic target and describe recent and current clinical trials examining CTSS inhibition as a means for treatment. Proteases in pulmonary diseases Research in the last 60 years has demonstrated that proteases are critical contributors to pulmonary disease pathophysiology. Initially known as protein-degrading enzymes with a restricted spectrum of substrates, recent studies have revealed that the diversity of protease substrates and biological effects triggered by their processing is vast [1, 2]. Proteases are primarily known for their matrix degradation capabilities, but also play significant roles in other biological mechanisms such as angiogenesis, growth factor bioavailability, cytokine processing, receptor shedding and activation, as well as cellular processes including migration, proliferation, invasion, and survival [3]. Importantly, protease activity requires tight regulation, and disruption of the close interplay between proteases, substrates and inhibitors may contribute to the pathogenesis and progression of a variety of pulmonary diseases, including muco-inflammatory diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), as well as infection [4]. In pulmonary diseases with a high neutrophil burden such as CF, a protease:antiprotease imbalance is frequently observed. The activity of proteases such as neutrophil elastase (NE) in the respiratory tract is regulated by antiproteases, such as α1-antitrypsin (A1AT) [5], secretory leukoprotease inhibitor (SLPI) [6] and elafin [7]. However, in diseases like CF, the antiproteases are overburdened by their cognate proteases and this imbalance can result in chronic airway inflammation, decreased mucociliary clearance, mucus obstruction, extracellular matrix (ECM) remodeling, increased susceptibility to infection and impaired immune responses [8].

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“…Cathepsin S (CTSS), a member of the histone family of enzymes, is highly expressed in renal clear cell carcinoma [25], hepatocellular carcinoma [26], cervical cancer [27], lung cancer [28] and other tumours and is an essential regulator of tumour growth and invasion. Suppression of cell migration and invasion by modulation of Ca 2+ -dependent downstream effectors after CTSS inhibition [29]. The expression of CTSS was regulated by PI3K/Akt and Ras/Raf/MAPK signalling pathways, is a candidate target for blocking the metastasis of breast and oral cancers [30,31].…”

Section: Discussionmentioning

confidence: 99%

Downregulation of CD44 Inhibits Proliferation, Invasion and Migration of Osteosarcoma Cells by Regulating the Expression of Cathepsin S

Kong

Gan

et al. 2021

Preprint

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BackgroundOsteosarcoma (OS) is a malignant bone tumour of mesenchymal origin. These tumours are characterised by rich vascularisation, therefore promoting rapid proliferation and facilitating metastasis. CD44 has been reported to be involved in OS, but its role and molecular mechanisms in the pathogenesis of the disease are not fully determined. MethodsIn this study, we investigated the antitumor effect of CD44 on the development of OS and further explored the molecular mechanisms. The expression of CD44, cathepsin S and MMP-9 was detected by Western blot (WB) and reverse transcription-polymerase chain reaction (RT-qPCR) in different cell lines (MG63, U2OS OS and hFOB 1.19). To elucidate the role of CD44 in OS, MG63 and U2OS cells were treated with small interference RNA (siRNA) to knock down CD44, and the knockdown efficiency was validated with GFP and RT-qPCR. Furthermore, cell proliferation was assayed using Cell Counting Kit‑8 (CCK-8) and colony formation assays, and cell migration and invasion were assayed by transwell and wound-healing assays. ResultsWe found that CD44 expression in the MG63 and U2OS OS cell lines was markedly increased compared to that of the human osteoblast hFOB 1.19 cell line. Knockdown of CD44 inhibited proliferation, migration, and invasion of MG63 and U2OS cells, possibly by regulating the expression of cathepsin S in OS. ConclusionTaken together, our data reinforced the evidence that CD44 knockdown inhibited cell proliferation, migration, and invasion of OS cells accompanied by altered expression of cathepsin S. These findings offer new clues for OS development and progression, suggesting CD44 as a potential therapeutic target for OS.

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Lysosomal cysteine protease cathepsin S is involved in cancer cell motility by regulating store-operated Ca2+ entry

Cited by 18 publications

References 46 publications

Inhibition of Cathepsin S Restores TGF-β-induced Epithelial-to-mesenchymal Transition and Tight Junction Turnover in Glioblastoma Cells

Inhibition of Cathepsin S Restores TGF-β-induced Epithelial-to-mesenchymal Transition and Tight Junction Turnover in Glioblastoma Cells

Cathepsin S: investigating an old player in lung disease pathogenesis, comorbidities, and potential therapeutics

Downregulation of CD44 Inhibits Proliferation, Invasion and Migration of Osteosarcoma Cells by Regulating the Expression of Cathepsin S

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