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Eriksson I, Öllinger K. Lysosomes in Cancer-At the Crossroad of Good and Evil. Cells 2024; 13:459. [PMID: 38474423 PMCID: PMC10930463 DOI: 10.3390/cells13050459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 02/27/2024] [Accepted: 03/01/2024] [Indexed: 03/14/2024] Open
Abstract
Although it has been known for decades that lysosomes are central for degradation and recycling in the cell, their pivotal role as nutrient sensing signaling hubs has recently become of central interest. Since lysosomes are highly dynamic and in constant change regarding content and intracellular position, fusion/fission events allow communication between organelles in the cell, as well as cell-to-cell communication via exocytosis of lysosomal content and release of extracellular vesicles. Lysosomes also mediate different forms of regulated cell death by permeabilization of the lysosomal membrane and release of their content to the cytosol. In cancer cells, lysosomal biogenesis and autophagy are increased to support the increased metabolism and allow growth even under nutrient- and oxygen-poor conditions. Tumor cells also induce exocytosis of lysosomal content to the extracellular space to promote invasion and metastasis. However, due to the enhanced lysosomal function, cancer cells are often more susceptible to lysosomal membrane permeabilization, providing an alternative strategy to induce cell death. This review summarizes the current knowledge of cancer-associated alterations in lysosomal structure and function and illustrates how lysosomal exocytosis and release of extracellular vesicles affect disease progression. We focus on functional differences depending on lysosomal localization and the regulation of intracellular transport, and lastly provide insight how new therapeutic strategies can exploit the power of the lysosome and improve cancer treatment.
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Affiliation(s)
- Ida Eriksson
- Division of Cell Biology, Department of Biomedical and Clinical Sciences, Linköping University, 58185 Linköping, Sweden;
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Stoka V, Vasiljeva O, Nakanishi H, Turk V. The Role of Cysteine Protease Cathepsins B, H, C, and X/Z in Neurodegenerative Diseases and Cancer. Int J Mol Sci 2023; 24:15613. [PMID: 37958596 PMCID: PMC10650516 DOI: 10.3390/ijms242115613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Revised: 10/17/2023] [Accepted: 10/18/2023] [Indexed: 11/15/2023] Open
Abstract
Papain-like cysteine proteases are composed of 11 human cysteine cathepsins, originally located in the lysosomes. They exhibit broad specificity and act as endopeptidases and/or exopeptidases. Among them, only cathepsins B, H, C, and X/Z exhibit exopeptidase activity. Recently, cysteine cathepsins have been found to be present outside the lysosomes and often participate in various pathological processes. Hence, they have been considered key signalling molecules. Their potentially hazardous proteolytic activities are tightly regulated. This review aims to discuss recent advances in understanding the structural aspects of these four cathepsins, mechanisms of their zymogen activation, regulation of their activities, and functional aspects of these enzymes in neurodegeneration and cancer. Neurodegenerative effects have been evaluated, particularly in Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, and neuropsychiatric disorders. Cysteine cathepsins also participate in tumour progression and metastasis through the overexpression and secretion of proteases, which trigger extracellular matrix degradation. To our knowledge, this is the first review to provide an in-depth analysis regarding the roles of cysteine cathepsins B, H, C, and X in neurodegenerative diseases and cancer. Further advances in understanding the functions of cysteine cathepsins in these conditions will result in the development of novel, targeted therapeutic strategies.
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Affiliation(s)
- Veronika Stoka
- Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, SI-1000 Ljubljana, Slovenia;
- Jožef Stefan International Postgraduate School, SI-1000 Ljubljana, Slovenia
| | - Olga Vasiljeva
- Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, SI-1000 Ljubljana, Slovenia;
- CytomX Therapeutics, Inc., South San Francisco, CA 94080, USA
| | - Hiroshi Nakanishi
- Department of Pharmacology, Faculty of Pharmacy, Yasuda Women’s University, Hiroshima 731-0153, Japan;
| | - Vito Turk
- Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, SI-1000 Ljubljana, Slovenia;
- Jožef Stefan International Postgraduate School, SI-1000 Ljubljana, Slovenia
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Li J, Tang M, Gao X, Tian S, Liu W. Mendelian randomization analyses explore the relationship between cathepsins and lung cancer. Commun Biol 2023; 6:1019. [PMID: 37805623 PMCID: PMC10560205 DOI: 10.1038/s42003-023-05408-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 10/02/2023] [Indexed: 10/09/2023] Open
Abstract
Lung cancer, a major contributor to cancer-related fatalities worldwide, involves a complex pathogenesis. Cathepsins, lysosomal cysteine proteases, play roles in various physiological and pathological processes, including tumorigenesis. Observational studies have suggested an association between cathepsins and lung cancer. However, the causal link between the cathepsin family and lung cancer remains undetermined. This study employed Mendelian randomization analyses to investigate this causal association. The univariable Mendelian randomization analysis results indicate that elevated cathepsin H levels increase the overall risk of lung cancer, adenocarcinoma, and lung cancer among smokers. Conversely, reverse Mendelian randomization analyses suggest that squamous carcinoma may lead to increased cathepsin B levels. A multivariable analysis using nine cathepsins as covariates reveals that elevated cathepsin H levels lead to an increased overall risk of lung cancer, adenocarcinoma, and lung cancer in smokers. In conclusion, cathepsin H may serve as a marker for lung cancer, potentially inspiring directions in lung cancer diagnosis and treatment.
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Affiliation(s)
- Jialin Li
- Department of Thoracic Surgery, The First Hospital of Jilin University, 1 Xinmin Street, Changchun, Jilin, 130021, PR China
| | - Mingbo Tang
- Department of Thoracic Surgery, The First Hospital of Jilin University, 1 Xinmin Street, Changchun, Jilin, 130021, PR China
| | - Xinliang Gao
- Department of Thoracic Surgery, The First Hospital of Jilin University, 1 Xinmin Street, Changchun, Jilin, 130021, PR China
| | - Suyan Tian
- Division of Clinical Research, The First Hospital of Jilin University, 1 Xinmin Street, Changchun, Jilin, 130021, PR China.
| | - Wei Liu
- Department of Thoracic Surgery, The First Hospital of Jilin University, 1 Xinmin Street, Changchun, Jilin, 130021, PR China.
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Meshko B, Volatier TLA, Hadrian K, Deng S, Hou Y, Kluth MA, Ganss C, Frank MH, Frank NY, Ksander B, Cursiefen C, Notara M. ABCB5+ Limbal Epithelial Stem Cells Inhibit Developmental but Promote Inflammatory (Lymph) Angiogenesis While Preventing Corneal Inflammation. Cells 2023; 12:1731. [PMID: 37443766 PMCID: PMC10341195 DOI: 10.3390/cells12131731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 06/16/2023] [Accepted: 06/20/2023] [Indexed: 07/15/2023] Open
Abstract
The limbus, the vascularized junction between the cornea and conjunctiva, is thought to function as a barrier against corneal neovascularization. However, the exact mechanisms regulating this remain unknown. In this study, the limbal epithelial stem cell (LESC) marker ABCB5 was used to investigate the role of LESCs in corneal neovascularization. In an ABCB5KO model, a mild but significant increase of limbal lymphatic and blood vascular network complexity was observed in developing mice (4 weeks) but not in adult mice. Conversely, when using a cornea suture model, the WT animals exhibited a mild but significant increase in the number of lymphatic vessel sprouts compared to the ABCB5KO, suggesting a contextual anti-lymphangiogenic effect of ABCB5 on the limbal vasculature during development, but a pro-lymphangiogenic effect under inflammatory challenge in adulthood. In addition, conditioned media from ABCB5-positive cultured human limbal epithelial cells (ABCB5+) stimulated human blood and lymphatic endothelial cell proliferation and migration. Finally, a proteomic analysis demonstrated ABCB5+ cells have a pro(lymph)angiogenic as well as an anti-inflammatory profile. These data suggest a novel dual, context-dependent role of ABCB5+ LESCs, inhibiting developmental but promoting inflammatory (lymph)angiogenesis in adulthood and exerting anti-inflammatory effects. These findings are of high clinical relevance in relation to LESC therapy against blindness.
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Affiliation(s)
- Berbang Meshko
- Department of Ophthalmology, University of Cologne, 50937 Cologne, Germany; (B.M.); (T.L.A.V.); (Y.H.)
| | - Thomas L. A. Volatier
- Department of Ophthalmology, University of Cologne, 50937 Cologne, Germany; (B.M.); (T.L.A.V.); (Y.H.)
| | - Karina Hadrian
- Department of Ophthalmology, University of Cologne, 50937 Cologne, Germany; (B.M.); (T.L.A.V.); (Y.H.)
| | - Shuya Deng
- Department of Ophthalmology, University of Cologne, 50937 Cologne, Germany; (B.M.); (T.L.A.V.); (Y.H.)
| | - Yanhong Hou
- Department of Ophthalmology, University of Cologne, 50937 Cologne, Germany; (B.M.); (T.L.A.V.); (Y.H.)
| | - Mark Andreas Kluth
- TICEBA GmbH, Im Neuenheimer Feld 517, 69120 Heidelberg, Germany; (M.A.K.); (C.G.)
- RHEACELL GmbH & Co. KG, Im Neuenheimer Feld 517, 69120 Heidelberg, Germany
| | - Christoph Ganss
- TICEBA GmbH, Im Neuenheimer Feld 517, 69120 Heidelberg, Germany; (M.A.K.); (C.G.)
- RHEACELL GmbH & Co. KG, Im Neuenheimer Feld 517, 69120 Heidelberg, Germany
| | - Markus H. Frank
- Transplant Research Program, Boston Children’s Hospital, Boston, MA 02115, USA
- Harvard Skin Disease Research Center, Department of Dermatology, Brigham and Women’s Hospital, Boston, MA 02115, USA
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA;
- School of Medical and Health Sciences, Edith Cowan University, Perth, WA 6027, Australia
| | - Natasha Y. Frank
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA;
- Department of Medicine, VA Boston Healthcare System, Boston, MA 02132, USA
- Division of Genetics, Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Bruce Ksander
- Massachusetts Eye & Ear Infirmary, Schepens Eye Research Institute, Boston, MA 02114, USA;
| | - Claus Cursiefen
- Department of Ophthalmology, University of Cologne, 50937 Cologne, Germany; (B.M.); (T.L.A.V.); (Y.H.)
- Institute for Genome Stability in Ageing and Disease, CECAD Research Center, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany
| | - Maria Notara
- Department of Ophthalmology, University of Cologne, 50937 Cologne, Germany; (B.M.); (T.L.A.V.); (Y.H.)
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50937 Cologne, Germany
- Institute for Genome Stability in Ageing and Disease, CECAD Research Center, Joseph-Stelzmann-Str. 26, 50931 Cologne, Germany
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Jiang H, Dong Z, Xia X, Li X. Cathepsins in oral diseases: mechanisms and therapeutic implications. Front Immunol 2023; 14:1203071. [PMID: 37334378 PMCID: PMC10272612 DOI: 10.3389/fimmu.2023.1203071] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 05/18/2023] [Indexed: 06/20/2023] Open
Abstract
Cathepsins are a type of lysosomal globulin hydrolase and are crucial for many physiological processes, including the resorption of bone matrix, innate immunity, apoptosis, proliferation, metastasis, autophagy, and angiogenesis. Findings regarding their functions in human physiological processes and disorders have drawn extensive attention. In this review, we will focus on the relationship between cathepsins and oral diseases. We highlight the structural and functional properties of cathepsins related to oral diseases, as well as the regulatory mechanisms in tissue and cells and their therapeutic uses. Elucidating the associated mechanism between cathepsins and oral diseases is thought to be a promising strategy for the treatment of oral diseases and may be a starting point for further studies at the molecular level.
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Affiliation(s)
- Hao Jiang
- Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
- School of Stomatology, Qingdao University, Qingdao, China
| | - Zuoxiang Dong
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
| | - Xiaomin Xia
- Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
- School of Stomatology, Qingdao University, Qingdao, China
| | - Xue Li
- Department of Stomatology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China
- School of Stomatology, Qingdao University, Qingdao, China
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Wang Y, Zhao J, Gu Y, Wang H, Jiang M, Zhao S, Qing H, Ni J. Cathepsin H: molecular characteristics and clues to function and mechanism. Biochem Pharmacol 2023; 212:115585. [PMID: 37148981 DOI: 10.1016/j.bcp.2023.115585] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 04/26/2023] [Accepted: 04/28/2023] [Indexed: 05/08/2023]
Abstract
Cathepsin H (CatH) is a lysosomal cysteine protease with a unique aminopeptidase activity that is extensively expressed in the lung, pancreas, thymus, kidney, liver, skin, and brain. Owing to its specific enzymatic activity, CatH has critical effects on the regulation of biological behaviours of cancer cells and pathological processes in brain diseases. Moreover, a neutral pH level is optimal for CatH activity, so it is expected to be active in the extra-lysosomal and extracellular space. In the present review, we describe the expression, maturation, and enzymatic properties of CatH, and summarize the available experimental evidence that mechanistically links CatH to various physiological and pathological processes. Finally, we discuss the challenges and potentials of CatH inhibitors in CatH-induced disease therapy.
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Affiliation(s)
- Yanfeng Wang
- Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, 100081, China
| | - Juan Zhao
- Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, 100081, China; Aerospace Medical Center, Aerospace Center Hospital, Beijing, 100081, China
| | - Yebo Gu
- Department of Stomatology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
| | - Haiping Wang
- School of Pharmaceutical Science, Nanjing Tech University, Nanjing, China
| | - Muzhou Jiang
- Department of Periodontics, Liaoning Provincial Key Laboratory of Oral Diseases, School and Hospital of Stomatology, China Medical University, Shenyang, 110002, China
| | - Shuxuan Zhao
- Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, 100081, China
| | - Hong Qing
- Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, 100081, China.
| | - Junjun Ni
- Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, 100081, China.
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Cathepsin H Knockdown Reverses Radioresistance of Hepatocellular Carcinoma via Metabolic Switch Followed by Apoptosis. Int J Mol Sci 2023; 24:ijms24065257. [PMID: 36982347 PMCID: PMC10049059 DOI: 10.3390/ijms24065257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 03/01/2023] [Indexed: 03/12/2023] Open
Abstract
Despite the wide application of radiotherapy in HCC, radiotherapy efficacy is sometimes limited due to radioresistance. Although radioresistance is reported with high glycolysis, the underlying mechanism between radioresistance and cancer metabolism, as well as the role of cathepsin H (CTSH) within it, remain unclear. In this study, tumor-bearing models and HCC cell lines were used to observe the effect of CTSH on radioresistance. Proteome mass spectrometry, followed by enrichment analysis, were used to investigate the cascades and targets regulated by CTSH. Technologies such as immunofluorescence co-localization flow cytometry and Western blot were used for further detection and verification. Through these methods, we originally found CTSH knockdown (KD) perturbed aerobic glycolysis and enhanced aerobic respiration, and thus promoted apoptosis through up-regulation and the release of proapoptotic factors such as AIFM1, HTRA2, and DIABLO, consequently reducing radioresistance. We also found that CTSH, together with its regulatory targets (such as PFKL, HK2, LDH, and AIFM1), was correlated with tumorigenesis and poor prognosis. In summary, our study found that the cancer metabolic switch and apoptosis were regulated by CTSH signaling, leading to the occurrence of radioresistance in HCC cells and suggesting the potential value of HCC diagnosis and therapy.
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Kos J, Mitrović A, Perišić Nanut M, Pišlar A. Lysosomal peptidases – Intriguing roles in cancer progression and neurodegeneration. FEBS Open Bio 2022; 12:708-738. [PMID: 35067006 PMCID: PMC8972049 DOI: 10.1002/2211-5463.13372] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 01/04/2022] [Accepted: 01/20/2022] [Indexed: 11/16/2022] Open
Abstract
Lysosomal peptidases are hydrolytic enzymes capable of digesting waste proteins that are targeted to lysosomes via endocytosis and autophagy. Besides intracellular protein catabolism, they play more specific roles in several other cellular processes and pathologies, either within lysosomes, upon secretion into the cell cytoplasm or extracellular space, or bound to the plasma membrane. In cancer, lysosomal peptidases are generally associated with disease progression, as they participate in crucial processes leading to changes in cell morphology, signaling, migration, and invasion, and finally metastasis. However, they can also enhance the mechanisms resulting in cancer regression, such as apoptosis of tumor cells or antitumor immune responses. Lysosomal peptidases have also been identified as hallmarks of aging and neurodegeneration, playing roles in oxidative stress, mitochondrial dysfunction, abnormal intercellular communication, dysregulated trafficking, and the deposition of protein aggregates in neuronal cells. Furthermore, deficiencies in lysosomal peptidases may result in other pathological states, such as lysosomal storage disease. The aim of this review was to highlight the role of lysosomal peptidases in particular pathological processes of cancer and neurodegeneration and to address the potential of lysosomal peptidases in diagnosing and treating patients.
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Affiliation(s)
- Janko Kos
- University of Ljubljana Faculty of Pharmacy Aškerčeva 7 1000 Ljubljana Slovenia
- Jožef Stefan Institute Department of Biotechnology Jamova 39 1000 Ljubljana Slovenia
| | - Ana Mitrović
- Jožef Stefan Institute Department of Biotechnology Jamova 39 1000 Ljubljana Slovenia
| | - Milica Perišić Nanut
- Jožef Stefan Institute Department of Biotechnology Jamova 39 1000 Ljubljana Slovenia
| | - Anja Pišlar
- University of Ljubljana Faculty of Pharmacy Aškerčeva 7 1000 Ljubljana Slovenia
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Peng P, Chen JY, Zheng K, Hu CH, Han YT. Favorable Prognostic Impact of Cathepsin H (CTSH) High Expression in Thyroid Carcinoma. Int J Gen Med 2021; 14:5287-5299. [PMID: 34522128 PMCID: PMC8434881 DOI: 10.2147/ijgm.s327689] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 08/26/2021] [Indexed: 12/13/2022] Open
Abstract
Background Presently, no study reported the function of cathepsin H (CTSH) in thyroid carcinoma (THCA). The aim of present study was to initially explore the factors affecting CTSH expression, and association between CTSH expression and survival rate in THCA. Methods We explored mRNA expression of CTSH in normal and BRCA tissues, and evaluated prognostic impact of CTSH expression on the overall survival of THCA patients. Then, related factors influencing CTSH mRNA expression in THCA were analyzed. Functional enrichment analysis was performed to reveal the potential function of CTSH involved in THCA. We also constructed PPI network among co-expressed genes of CTSH to determine hub genes, followed by association analysis on hub genes with CTSH. Results (1) CTSH mRNA was highly expressed in THCA compared with normal group (P<0.001). High expression of CTSH was conducive to the overall survival of THCA patients (P=0.0027). CTSH was then determined as an independent prognostic factor in THCA (P=0.024). (2) The mRNA expression of CTSH was statistically related to patient’s histological type, N stage, T stage, tumor stage and sample type (all P<0.001). CTSH copy number variation and methylation also influenced its mRNA expression (all P<0.001). (3) Pathway analysis indicated that CTSH mainly participated in cancer-related pathways, such as hedgehog signaling pathway, cytokine–cytokine receptor interaction and JAK-STAT signaling pathway (all P<0.05). (4) The top 10 co-expressed genes in whole PPI network showed significant correlation with CTSH expression (all P<0.001). Conclusion CTSH higher expression was observed in THCA, which caused a good prognosis of patients. CTSH expression might be regulated by multiple factors including clinical characteristic, methylation, copy number and other genes. This study demonstrated the clinical significance of CTSH in THCA, as well as revealed the potential pathway associated with CTSH involved in thyroid cancer.
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Affiliation(s)
- Pai Peng
- Department of Breast and Thyroid Surgery, Xiaogan Central Hospital&Xiaogan Hospital Affiliated to Wuhan University of Science and Technology, Xiaogan, 432000, People's Republic of China
| | - Jiang-Yuan Chen
- School of Medicine, Jianghan University, Wuhan, 430000, People's Republic of China
| | - Kai Zheng
- School of Medicine, Wuhan University of Science and Technology, Wuhan, 430000, People's Republic of China
| | - Chao-Hua Hu
- Department of Breast and Thyroid Surgery, Xiaogan Central Hospital&Xiaogan Hospital Affiliated to Wuhan University of Science and Technology, Xiaogan, 432000, People's Republic of China
| | - Yun-Tao Han
- Department of Breast and Thyroid Surgery, Xiaogan Central Hospital&Xiaogan Hospital Affiliated to Wuhan University of Science and Technology, Xiaogan, 432000, People's Republic of China
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Zhang Z, Yue P, Lu T, Wang Y, Wei Y, Wei X. Role of lysosomes in physiological activities, diseases, and therapy. J Hematol Oncol 2021; 14:79. [PMID: 33990205 PMCID: PMC8120021 DOI: 10.1186/s13045-021-01087-1] [Citation(s) in RCA: 159] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Accepted: 05/03/2021] [Indexed: 02/07/2023] Open
Abstract
Long known as digestive organelles, lysosomes have now emerged as multifaceted centers responsible for degradation, nutrient sensing, and immunity. Growing evidence also implicates role of lysosome-related mechanisms in pathologic process. In this review, we discuss physiological function of lysosomes and, more importantly, how the homeostasis of lysosomes is disrupted in several diseases, including atherosclerosis, neurodegenerative diseases, autoimmune disorders, pancreatitis, lysosomal storage disorders, and malignant tumors. In atherosclerosis and Gaucher disease, dysfunction of lysosomes changes cytokine secretion from macrophages, partially through inflammasome activation. In neurodegenerative diseases, defect autophagy facilitates accumulation of toxic protein and dysfunctional organelles leading to neuron death. Lysosomal dysfunction has been demonstrated in pathology of pancreatitis. Abnormal autophagy activation or inhibition has been revealed in autoimmune disorders. In tumor microenvironment, malignant phenotypes, including tumorigenesis, growth regulation, invasion, drug resistance, and radiotherapy resistance, of tumor cells and behaviors of tumor-associated macrophages, fibroblasts, dendritic cells, and T cells are also mediated by lysosomes. Based on these findings, a series of therapeutic methods targeting lysosomal proteins and processes have been developed from bench to bedside. In a word, present researches corroborate lysosomes to be pivotal organelles for understanding pathology of atherosclerosis, neurodegenerative diseases, autoimmune disorders, pancreatitis, and lysosomal storage disorders, and malignant tumors and developing novel therapeutic strategies.
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Affiliation(s)
- Ziqi Zhang
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan People’s Republic of China
| | - Pengfei Yue
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan People’s Republic of China
| | - Tianqi Lu
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan People’s Republic of China
| | - Yang Wang
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan People’s Republic of China
| | - Yuquan Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan People’s Republic of China
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041 Sichuan People’s Republic of China
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Hölzen L, Parigiani MA, Reinheckel T. Tumor cell- and microenvironment-specific roles of cysteine cathepsins in mouse models of human cancers. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2020; 1868:140423. [PMID: 32247787 DOI: 10.1016/j.bbapap.2020.140423] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Revised: 03/20/2020] [Accepted: 03/29/2020] [Indexed: 12/22/2022]
Abstract
The human genome encodes for 11 papain-like endolysosomal cysteine peptidases, collectively known as the cysteine cathepsins. Based on their biochemical properties and with the help of experiments in cell culture, the cysteine cathepsins have acquired a reputation as promotors of progression and metastasis of various cancer entities. However, tumors are known to be complex tissues in which non-cancerous cells are also critical for tumorigenesis. Here we discuss the results of the intense investigation of cathepsins in mouse models of human cancers. We focus on models in immunocompetent mice, because only such models allow for analysis of cathepsins in a fully functional tumor microenvironment. An important outcome of those studies was the identification of cancer-promoting cathepsins in tumor-associated macrophages. Another interesting outcome of these animal studies was the identification of a homeostatic tumor-suppressive role for cathepsin L in skin and intestinal cancers. Taken together, these in vivo findings provide a basis for the use of cysteine cathepsins as therapeutic targets, prodrug activators, or as proteases for imaging tumors.
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Affiliation(s)
- Lena Hölzen
- Institute of Molecular Medicine and Cell Research, Medical Faculty, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany; German Cancer Research Center (DKFZ), Heidelberg, German Cancer Consortium (DKTK), Partner Site, Freiburg, Germany
| | - Maria Alejandra Parigiani
- Institute of Molecular Medicine and Cell Research, Medical Faculty, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Thomas Reinheckel
- Institute of Molecular Medicine and Cell Research, Medical Faculty, University of Freiburg, Freiburg, Germany; German Cancer Research Center (DKFZ), Heidelberg, German Cancer Consortium (DKTK), Partner Site, Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
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Metformin ameliorates stress-induced depression-like behaviors via enhancing the expression of BDNF by activating AMPK/CREB-mediated histone acetylation. J Affect Disord 2020; 260:302-313. [PMID: 31521867 DOI: 10.1016/j.jad.2019.09.013] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2019] [Revised: 07/22/2019] [Accepted: 09/02/2019] [Indexed: 12/21/2022]
Abstract
BACKGROUND Metformin, a first-line antiglycemic drug, has been reported to have anti-depressant effects in patients with type 2 diabetes; however, its exact role and underlying mechanism still need to be investigated. METHOD C57BL/6J mice were subjected to the Chronic social defeat stress (SDS) and drug administration (Control + Vehicle, SDS + Vehicle, SDS + MET (200 mg kg-1), SDS + FLUOX (3 mg kg-1), SDS + MET + FLUOX). And the depression phenotypes were evaluated by the sucrose preference test, social interaction, tail suspension test and forced swimming test. The potential mechanisms underlying the effects of metformin on depression was discussed by using Chromatin immunoprecipitation, Quantitative real-time PCR mRNA expression analysis and Western blot in vivo and in primary cultured hippocampal neurons. RESULT The metformin treatment counteracted the development of depression-like behaviors in mice suffering SDS when administered alone and enhanced the anti-depressant effect of fluoxetine when combined with fluoxetine. Further RNA sequencing analysis revealed that metformin treatment prevented the transcriptional changes in the medial prefrontal cortex (mPFC) of the animals and Golgi staining indicated favorable morphological changes in the neurite plasticity of CA1 pyramidal neurons, which approximated to those found in unstressed mice. At a molecular level, metformin significantly upregulated the expression of the brain-derived neurotrophic factor (BDNF) by increasing the histone acetylation along with the BDNF promoter, which was attributed to the activation of AMP-activated protein kinase (AMPK) and cAMP-response element binding protein (CREB). CONCLUSION Our findings suggest that metformin can produce antidepressant effects, which provides empirical insights into the clinical value of metformin in the prevention and therapy of depression.
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13
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Rudzińska M, Parodi A, Soond SM, Vinarov AZ, Korolev DO, Morozov AO, Daglioglu C, Tutar Y, Zamyatnin AA. The Role of Cysteine Cathepsins in Cancer Progression and Drug Resistance. Int J Mol Sci 2019; 20:E3602. [PMID: 31340550 PMCID: PMC6678516 DOI: 10.3390/ijms20143602] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 07/17/2019] [Accepted: 07/19/2019] [Indexed: 12/21/2022] Open
Abstract
Cysteine cathepsins are lysosomal enzymes belonging to the papain family. Their expression is misregulated in a wide variety of tumors, and ample data prove their involvement in cancer progression, angiogenesis, metastasis, and in the occurrence of drug resistance. However, while their overexpression is usually associated with highly aggressive tumor phenotypes, their mechanistic role in cancer progression is still to be determined to develop new therapeutic strategies. In this review, we highlight the literature related to the role of the cysteine cathepsins in cancer biology, with particular emphasis on their input into tumor biology.
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Affiliation(s)
- Magdalena Rudzińska
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, 119991 Moscow, Russia
| | - Alessandro Parodi
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, 119991 Moscow, Russia
| | - Surinder M Soond
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, 119991 Moscow, Russia
| | - Andrey Z Vinarov
- Institute for Urology and Reproductive Health, Sechenov University, 119992 Moscow, Russia
| | - Dmitry O Korolev
- Institute for Urology and Reproductive Health, Sechenov University, 119992 Moscow, Russia
| | - Andrey O Morozov
- Institute for Urology and Reproductive Health, Sechenov University, 119992 Moscow, Russia
| | - Cenk Daglioglu
- Izmir Institute of Technology, Faculty of Science, Department of Molecular Biology and Genetics, 35430 Urla/Izmir, Turkey
| | - Yusuf Tutar
- Faculty of Pharmacy, University of Health Sciences, 34668 Istanbul, Turkey
| | - Andrey A Zamyatnin
- Institute of Molecular Medicine, Sechenov First Moscow State Medical University, 119991 Moscow, Russia.
- Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia.
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14
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Kalamegam G, Sait KHW, Anfinan N, Kadam R, Ahmed F, Rasool M, Naseer MI, Pushparaj PN, Al-Qahtani M. Cytokines secreted by human Wharton's jelly stem cells inhibit the proliferation of ovarian cancer (OVCAR3) cells in vitro. Oncol Lett 2019; 17:4521-4531. [PMID: 30944641 PMCID: PMC6444458 DOI: 10.3892/ol.2019.10094] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Accepted: 01/23/2019] [Indexed: 12/27/2022] Open
Abstract
Cytokines enhance tumour cell recognition via cytotoxic effector cells and are therefore effectively used in cancer immunotherapy. Mesenchymal stem cells have efficient homing potential and have been used to target and inhibit various types of cancer mediated by the release of soluble/bioactive factors. Initial evaluation of the human Wharton's jelly stem cell conditioned medium (hWJSC-CM) and cell lysate (hWJSC-CL) against an ovarian cancer cell line (OVCAR3) demonstrated their inhibitory effect in vitro. The secreted cytokine profile was then studied to understand whether the OVCAR3 inhibitory effect was mediated by the cytokines. Expression of cytokines in OVCAR3 following 48 h treatment with hWJSC extracts, namely the hWJSC-CM (50%) and hWJSC-CL (10 µg/ml), was evaluated using multiplex cytokine assay. Paclitaxel (5 nM) was used as a positive control. Cytokines tumour necrosis factor α, interleukin (IL)-4, IL-6, IL-8, IL-10, IL-13, IL-17, IL-1β and granulocyte colony-stimulating factor, reported to be involved in tumour growth, invasion and migration, were significantly decreased. Cytokines with antitumour effects, namely IL-1 receptor antagonist (IL-1RA), IL-2, IL-2 receptor, IL-5, IL-7, IL-12, IL-15, interferon (IFN)-α and IFN-γ, were mildly increased or decreased. Only the increases in IL-1RA (with paclitaxel, hWJSC-CM and hWJSC-CL) and granulocyte-macrophage colony-stimulating factor (with hWJSC-CL) were statistically significant. The chemokines monocyte chemoattractant protein 1, macrophage inflammatory protein (MIP)-1α, MIP-1β and Regulated Upon Activation, Normally T-Expressed, and Secreted were significantly decreased while monokine induced by IFN-γ, IFN-γ induced protein 10 and Eotaxin demonstrated mild decreases. The growth factors basic fibroblast growth factor, vascular endothelial growth factor and hepatocyte growth factor were significantly decreased. Heatmaps demonstrated differential fold changes in cytokines and hierarchical cluster analysis revealed 3 major and 7 minor sub-clusters of associated cytokines, chemokines and growth factors. In conclusion, the hWJSC extracts decreased the expression of oncogenic cytokines, chemokines and growth factors, which mediated the inhibition of OVCAR3 cells in vitro.
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Affiliation(s)
- Gauthaman Kalamegam
- Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah 21589, Kingdom of Saudi Arabia.,Faculty of Medicine, AIMST University, Bedong, Kedah 08100, Malaysia
| | - Khalid Hussein Wali Sait
- Department of Obstetrics and Gynaecology, Faculty of Medicine, King Abdulaziz University Hospital, Jeddah 22252, Kingdom of Saudi Arabia
| | - Nisreen Anfinan
- Department of Obstetrics and Gynaecology, Faculty of Medicine, King Abdulaziz University Hospital, Jeddah 22252, Kingdom of Saudi Arabia
| | - Roaa Kadam
- Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah 21589, Kingdom of Saudi Arabia
| | - Farid Ahmed
- Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah 21589, Kingdom of Saudi Arabia
| | - Mahmood Rasool
- Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah 21589, Kingdom of Saudi Arabia
| | - Mohammad Imran Naseer
- Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah 21589, Kingdom of Saudi Arabia
| | - Peter Natesan Pushparaj
- Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah 21589, Kingdom of Saudi Arabia
| | - Mohammed Al-Qahtani
- Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah 21589, Kingdom of Saudi Arabia
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15
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Krug S, Abbassi R, Griesmann H, Sipos B, Wiese D, Rexin P, Blank A, Perren A, Haybaeck J, Hüttelmaier S, Rinke A, Gress TM, Michl P. Therapeutic targeting of tumor-associated macrophages in pancreatic neuroendocrine tumors. Int J Cancer 2019; 143:1806-1816. [PMID: 29696624 DOI: 10.1002/ijc.31562] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 03/18/2018] [Accepted: 03/28/2018] [Indexed: 12/13/2022]
Abstract
Pancreatic neuroendocrine tumors (PNETs) represent a heterogeneous group of neuroendocrine neoplasms with varying biological behavior and response to treatment. Although targeted therapies have been shown to improve the survival for patients at advanced stage, resistance to current therapies frequently occurs during the course of therapy. Previous reports indicate that the infiltration of tumor-associated macrophages (TAMs) in PNETs might correlate with tumor progression and metastasis formation. We aimed to evaluate the prognostic and functional impact of TAMs in human PNETs in vitro and in vivo and to investigate the effect of therapeutic targeting TAMs in a genetic PNET mouse model. TAM expression pattern was assessed immunohistochemically in human PNET tissue sections and a tissue-micro-array of PNET tumors with different functionality, stage, and grading. The effect of liposomal clodronate on TAM cell viability was analyzed in myeloid cell lines and isolated murine bone macrophages (mBMM). In vivo, RIP1Tag2 mice developing insulinomas were treated with liposomal clodronate or PBS-Liposomes. Tumor progression, angiogenesis and immune cell infiltration were assessed by immunohistochemistry. In human, insulinomas TAM density was correlated with invasiveness and malignant behavior. Moreover, TAM infiltration in liver metastases was significantly increased compared to primary tumors. In vitro, Liposomal clodronate selectively inhibited the viability of myeloid cells and murine bone macrophages, leaving PNET tumor cell lines largely unaffected. In vivo, repeated application of liposomal clodronate to RIP1Tag2 mice significantly diminished the malignant transformation of insulinomas, which was accompanied by a reduced infiltration of F4/80-positive TAM cells and simultaneously by a decreased microvessel density, suggesting a pronounced effect of clodronate-induced myeloid depletion on tumor angiogenesis. Concomitant treatment with the antiangiogenic TKI sunitinib, however, did not show any synergistic effects with liposomal clodronate. TAMs are crucial for malignant transformation in human PNET and correlate with metastatic behavior. Pharmacological targeting of TAMs via liposomal clodronate disrupts tumor progression in the RIP1Tag2 neuroendocrine tumor model and was associated with reduced tumor angiogenesis. Based on these results, using liposomal clodronate to target proangiogenic myeloid cells could be employed as novel therapeutic avenue in highly angiogenic tumors such as PNET.
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Affiliation(s)
- Sebastian Krug
- Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, Halle, Saale, Germany
| | - Rami Abbassi
- Department of Gastroenterology and Endocrinology, Philipps-University, Marburg, Germany
| | - Heidi Griesmann
- Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, Halle, Saale, Germany
| | - Bence Sipos
- Institute of Pathology and Neuropathology, University Hospital of Tübingen, Tübingen, Germany
| | - Dominik Wiese
- Department of Visceral, Thoracic and Vascular Surgery, Philipps-University, Marburg, Germany
| | - Peter Rexin
- Institute of Pathology, Philipps-University, Marburg, Germany
| | - Annika Blank
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Aurel Perren
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Johannes Haybaeck
- Department of Pathology, Otto-von-Guericke-University, Magdeburg, Germany
| | - Stefan Hüttelmaier
- Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, Halle, Saale, Germany
| | - Anja Rinke
- Department of Gastroenterology and Endocrinology, Philipps-University, Marburg, Germany
| | - Thomas M Gress
- Department of Gastroenterology and Endocrinology, Philipps-University, Marburg, Germany
| | - Patrick Michl
- Department of Internal Medicine I, Martin Luther University Halle-Wittenberg, Halle, Saale, Germany
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16
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Roger M, Martínez J, Peiró G, Aparicio JR, Ruiz F, Compañy L, Casellas JA. EUS-FNA cytological material from pancreatic lesions: the expression of cathepsins and its predictive value of malignancy. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2018; 110:446-450. [PMID: 29893579 DOI: 10.17235/reed.2018.4200/2016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
AIMS To assess the expression of cathepsins in pancreatic samples obtained by endoscopic ultrasonography and fine needle aspiration (EUS-FNA) and to investigate their relationship with the staging of the pancreatic ductal adenocarcinoma (PDAC). METHODS We prospectively included patients with solid pancreatic masses, in which EUS-FNA were performed. Cathepsins B, L, S and H expression was determined in FNA samples. RESULTS Seventeen FNA were performed. All cytological material was from PDAC. Expression of cathepsins was predominantly low (B 65%, L 23%, S 76%, and H 41%). We found no correlation between the expression levels and the extension of the neoplasm. CONCLUSION Expression of cathepsins in the cytological material of PDAC is diverse but still poor to be useful in the pre-operative diagnosis. There is no correlation between the expression levels of cathepsins and the extension of the PDAC.
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Affiliation(s)
- Manuela Roger
- Unidad de Endoscopia Digestiva, Hospital General Universitario de Alicante, España
| | - Juan Martínez
- Unidad de Endoscopia Digestiva, Hospital General Universitario de Alicante
| | - Gloria Peiró
- Servicio de Anatomía Patológica, Hospital General Universitario de Alicante
| | | | - Francisco Ruiz
- Unidad de Endoscopia Digestiva, Hospital General Universitario de Alicante, España
| | - Luís Compañy
- Unidad de Endoscopia Digestiva, Hospital General Universitario de Alicante, España
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17
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Cysteine cathepsins as a prospective target for anticancer therapies-current progress and prospects. Biochimie 2018; 151:85-106. [PMID: 29870804 DOI: 10.1016/j.biochi.2018.05.023] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 05/31/2018] [Indexed: 02/08/2023]
Abstract
Cysteine cathepsins (CTS), being involved in both physiological and pathological processes, play an important role in the human body. During the last 30 years, it has been shown that CTS are highly upregulated in a wide variety of cancer types although they have received a little attention as a potential therapeutic target as compared to serine or metalloproteinases. Studies on the increasing problem of neoplastic progression have revealed that secretion of cell-surface- and intracellular cysteine proteases is aberrant in tumor cells and has an impact on their growth, invasion, and metastasis by taking part in tumor angiogenesis, in apoptosis, and in events of inflammatory and immune responses. Considering the role of CTS in carcinogenesis, inhibition of these enzymes becomes an attractive strategy for cancer therapy. The downregulation of natural CTS inhibitors (CTSsis), such as cystatins, observed in various types of cancer, supports this claim. The intention of this review is to highlight the relationship of CTS with cancer and to present illustrations that explain how some of their inhibitors affect processes related to neoplastic progression.
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18
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Kenyon A, Gavriouchkina D, Zorman J, Chong-Morrison V, Napolitani G, Cerundolo V, Sauka-Spengler T. Generation of a double binary transgenic zebrafish model to study myeloid gene regulation in response to oncogene activation in melanocytes. Dis Model Mech 2018; 11:dmm030056. [PMID: 29666124 PMCID: PMC5963855 DOI: 10.1242/dmm.030056] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 02/01/2018] [Indexed: 12/11/2022] Open
Abstract
A complex network of inflammatory genes is closely linked to somatic cell transformation and malignant disease. Immune cells and their associated molecules are responsible for detecting and eliminating cancer cells as they establish themselves as the precursors of a tumour. By the time a patient has a detectable solid tumour, cancer cells have escaped the initial immune response mechanisms. Here, we describe the development of a double binary zebrafish model that enables regulatory programming of the myeloid cells as they respond to oncogene-activated melanocytes to be explored, focussing on the initial phase when cells become the precursors of cancer. A hormone-inducible binary system allows for temporal control of expression of different Ras oncogenes (NRasQ61K, HRasG12V and KRasG12V) in melanocytes, leading to proliferation and changes in morphology of the melanocytes. This model was coupled to binary cell-specific biotagging models allowing in vivo biotinylation and subsequent isolation of macrophage or neutrophil nuclei for regulatory profiling of their active transcriptomes. Nuclear transcriptional profiling of neutrophils, performed as they respond to the earliest precursors of melanoma in vivo, revealed an intricate landscape of regulatory factors that may promote progression to melanoma, including Serpinb1l4, Fgf1, Fgf6, Cathepsin H, Galectin 1 and Galectin 3. The model presented here provides a powerful platform to study the myeloid response to the earliest precursors of melanoma.
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Affiliation(s)
- Amy Kenyon
- University of Oxford, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, Oxford OX3 9DS, United Kingdom
- University of Oxford, Weatherall Institute of Molecular Medicine, MRC Human Immunology Unit, Radcliffe Department of Medicine, Oxford OX3 9DS, United Kingdom
| | - Daria Gavriouchkina
- University of Oxford, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, Oxford OX3 9DS, United Kingdom
| | - Jernej Zorman
- University of Oxford, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, Oxford OX3 9DS, United Kingdom
| | - Vanessa Chong-Morrison
- University of Oxford, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, Oxford OX3 9DS, United Kingdom
| | - Giorgio Napolitani
- University of Oxford, Weatherall Institute of Molecular Medicine, MRC Human Immunology Unit, Radcliffe Department of Medicine, Oxford OX3 9DS, United Kingdom
| | - Vincenzo Cerundolo
- University of Oxford, Weatherall Institute of Molecular Medicine, MRC Human Immunology Unit, Radcliffe Department of Medicine, Oxford OX3 9DS, United Kingdom
| | - Tatjana Sauka-Spengler
- University of Oxford, Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, Oxford OX3 9DS, United Kingdom
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19
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Varol C, Sagi I. Phagocyte-extracellular matrix crosstalk empowers tumor development and dissemination. FEBS J 2017; 285:734-751. [DOI: 10.1111/febs.14317] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 10/01/2017] [Accepted: 10/31/2017] [Indexed: 12/15/2022]
Affiliation(s)
- Chen Varol
- The Research Center for Digestive Tract and Liver Diseases; Tel-Aviv Sourasky Medical Center; Sackler Faculty of Medicine; Tel-Aviv University; Israel
- Department of Clinical Microbiology and Immunology; Sackler Faculty of Medicine; Tel Aviv University; Israel
| | - Irit Sagi
- Department of Biological Regulation; Weizmann Institute of Science; Rehovot Israel
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20
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Yan D, Wang HW, Bowman RL, Joyce JA. STAT3 and STAT6 Signaling Pathways Synergize to Promote Cathepsin Secretion from Macrophages via IRE1α Activation. Cell Rep 2017; 16:2914-2927. [PMID: 27626662 DOI: 10.1016/j.celrep.2016.08.035] [Citation(s) in RCA: 118] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Revised: 07/13/2016] [Accepted: 08/11/2016] [Indexed: 12/21/2022] Open
Abstract
Tumor-associated macrophages play critical roles during tumor progression by promoting angiogenesis, cancer cell proliferation, invasion, and metastasis. Cysteine cathepsin proteases, produced by macrophages and cancer cells, modulate these processes, but it remains unclear how these typically lysosomal enzymes are regulated and secreted within the tumor microenvironment. Here, we identify a STAT3 and STAT6 synergy that potently upregulates cathepsin secretion by macrophages via engagement of an unfolded protein response (UPR) pathway. Whole-genome expression analyses revealed that the TH2 cytokine interleukin (IL)-4 synergizes with IL-6 or IL-10 to activate UPR via STAT6 and STAT3. Pharmacological inhibition of the UPR sensor IRE1α blocks cathepsin secretion and blunts macrophage-mediated cancer cell invasion. Similarly, genetic deletion of STAT3 and STAT6 signaling components impairs tumor development and invasion in vivo. Together, these findings demonstrate that cytokine-activated STAT3 and STAT6 cooperate in macrophages to promote a secretory phenotype that enhances tumor progression in a cathepsin-dependent manner.
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Affiliation(s)
- Dongyao Yan
- Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | - Hao-Wei Wang
- Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | - Robert L Bowman
- Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | - Johanna A Joyce
- Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Ludwig Institute for Cancer Research, University of Lausanne, 1066 Lausanne, Switzerland; Department of Oncology, University of Lausanne, 1066 Lausanne, Switzerland.
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21
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Raghav N, Singh M. SAR studies of some acetophenone phenylhydrazone based pyrazole derivatives as anticathepsin agents. Bioorg Chem 2017; 75:38-49. [PMID: 28915464 DOI: 10.1016/j.bioorg.2017.08.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Revised: 08/18/2017] [Accepted: 08/19/2017] [Indexed: 12/12/2022]
Abstract
Cathepsins have emerged as promising molecular targets in a number of diseases such as Alzeimer's, inflammation and cancer. Elevated cathepsin's levels and decreased cellular inhibitor concentrations have emphasized the search for novel inhibitors of cathepsins. The present work is focused on the design and synthesis of some acetophenone phenylhydrazone based pyrazole derivatives as novel non peptidyl inhibitors of cathepsins B, H and L. The synthesized compounds after characterization have been explored for their inhibitory potency against cathepsins B, H and L. The results show that some of the synthesized compounds exhibit anti-catheptic activity with Ki value of the order of 10-10M. Differential inhibitory effects have been observed for cathepsins B, H and L. Cathepsin L is inhibited more pronounced than cathepsin B and cathepsin H in that order.
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Affiliation(s)
- Neera Raghav
- Department of Chemistry, Kurukshetra University, Kurukshetra 136119, India.
| | - Mamta Singh
- Department of Chemistry, Kurukshetra University, Kurukshetra 136119, India
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22
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Cystatin C deficiency suppresses tumor growth in a breast cancer model through decreased proliferation of tumor cells. Oncotarget 2017; 8:73793-73809. [PMID: 29088746 PMCID: PMC5650301 DOI: 10.18632/oncotarget.17379] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 03/22/2017] [Indexed: 01/01/2023] Open
Abstract
Cysteine cathepsins are proteases that, in addition to their important physiological functions, have been associated with multiple pathologies, including cancer. Cystatin C (CstC) is a major endogenous inhibitor that regulates the extracellular activity of cysteine cathepsins. We investigated the role of cystatin C in mammary cancer using CstC knockout mice and a mouse model of breast cancer induced by expression of the polyoma middle T oncoprotein (PyMT) in the mammary epithelium. We showed that the ablation of CstC reduced the rate of mammary tumor growth. Notably, a decrease in the proliferation of CstC knockout PyMT tumor cells was demonstrated ex vivo and in vitro, indicating a role for this protease inhibitor in signaling pathways that control cell proliferation. An increase in phosphorylated p-38 was observed in CstC knockout tumors, suggesting a novel function for cystatin C in cancer development, independent of the TGF-β pathway. Moreover, proteomic analysis of the CstC wild-type and knockout PyMT primary cell secretomes revealed a decrease in the levels of 14-3-3 proteins in the secretome of knock-out cells, suggesting a novel link between cysteine cathepsins, cystatin C and 14-3-3 proteins in tumorigenesis, calling for further investigations.
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23
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Ketterer S, Gomez-Auli A, Hillebrand LE, Petrera A, Ketscher A, Reinheckel T. Inherited diseases caused by mutations in cathepsin protease genes. FEBS J 2017; 284:1437-1454. [PMID: 27926992 DOI: 10.1111/febs.13980] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Revised: 11/11/2016] [Accepted: 11/29/2016] [Indexed: 02/07/2023]
Abstract
Lysosomal cathepsins are proteolytic enzymes increasingly recognized as prognostic markers and potential therapeutic targets in a variety of diseases. In those conditions, the cathepsins are mostly overexpressed, thereby driving the respective pathogenic processes. Although less known, there are also diseases with a genetic deficiency of cathepsins. In fact, nowadays 6 of the 15 human proteases called 'cathepsins' have been linked to inherited syndromes. However, only three of these syndromes are typical lysosomal storage diseases, while the others are apparently caused by defective cleavage of specific protein substrates. Here, we will provide an introduction on lysosomal cathepsins, followed by a brief description of the clinical symptoms of the various genetic diseases. For each disease, we focus on the known mutations of which many have been only recently identified by modern genome sequencing approaches. We further discuss the effect of the respective mutation on protease structure and activity, the resulting pathogenesis, and possible therapeutic strategies.
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Affiliation(s)
- Stephanie Ketterer
- Medical Faculty, Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Germany.,Faculty of Biology, Albert-Ludwigs-University Freiburg, Germany
| | - Alejandro Gomez-Auli
- Medical Faculty, Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Germany.,Faculty of Biology, Albert-Ludwigs-University Freiburg, Germany.,Spemann Graduate School of Biology and Medicine (SGBM), Albert-Ludwigs-University Freiburg, Germany
| | - Larissa E Hillebrand
- Medical Faculty, Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Germany.,Faculty of Biology, Albert-Ludwigs-University Freiburg, Germany.,BIOSS Centre for Biological Signalling Studies, Freiburg, Germany
| | - Agnese Petrera
- Medical Faculty, Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Germany
| | - Anett Ketscher
- Medical Faculty, Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Germany
| | - Thomas Reinheckel
- Medical Faculty, Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Germany.,BIOSS Centre for Biological Signalling Studies, Freiburg, Germany
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24
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Kirby MK, Ramaker RC, Gertz J, Davis NS, Johnston BE, Oliver PG, Sexton KC, Greeno EW, Christein JD, Heslin MJ, Posey JA, Grizzle WE, Vickers SM, Buchsbaum DJ, Cooper SJ, Myers RM. RNA sequencing of pancreatic adenocarcinoma tumors yields novel expression patterns associated with long-term survival and reveals a role for ANGPTL4. Mol Oncol 2016; 10:1169-82. [PMID: 27282075 PMCID: PMC5423196 DOI: 10.1016/j.molonc.2016.05.004] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Revised: 04/25/2016] [Accepted: 05/17/2016] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Pancreatic adenocarcinoma patients have low survival rates due to late-stage diagnosis and high rates of cancer recurrence even after surgical resection. It is important to understand the molecular characteristics associated with survival differences in pancreatic adenocarcinoma tumors that may inform patient care. RESULTS RNA sequencing was performed for 51 patient tumor tissues extracted from patients undergoing surgical resection, and expression was associated with overall survival time from diagnosis. Our analysis uncovered 323 transcripts whose expression correlates with survival time in our pancreatic patient cohort. This genomic signature was validated in an independent RNA-seq dataset of 68 additional patients from the International Cancer Genome Consortium. We demonstrate that this transcriptional profile is largely independent of markers of cellular division and present a 19-transcript predictive model built from a subset of the 323 transcripts that can distinguish patients with differing survival times across both the training and validation patient cohorts. We present evidence that a subset of the survival-associated transcripts is associated with resistance to gemcitabine treatment in vitro, and reveal that reduced expression of one of the survival-associated transcripts, Angiopoietin-like 4, impairs growth of a gemcitabine-resistant pancreatic cancer cell line. CONCLUSIONS Gene expression patterns in pancreatic adenocarcinoma tumors can distinguish patients with differing survival outcomes after undergoing surgical resection, and the survival difference could be associated with the intrinsic gemcitabine sensitivity of primary patient tumors. Thus, these transcriptional differences may impact patient care by distinguishing patients who would benefit from a non-gemcitabine based therapy.
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Affiliation(s)
- Marie K Kirby
- HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
| | - Ryne C Ramaker
- HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA; University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jason Gertz
- HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
| | | | | | - Patsy G Oliver
- University of Alabama at Birmingham, Birmingham, AL, USA
| | | | | | | | | | - James A Posey
- University of Alabama at Birmingham, Birmingham, AL, USA
| | | | | | | | - Sara J Cooper
- HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA
| | - Richard M Myers
- HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
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TAILS N-Terminomics and Proteomics Show Protein Degradation Dominates over Proteolytic Processing by Cathepsins in Pancreatic Tumors. Cell Rep 2016; 16:1762-1773. [PMID: 27477282 DOI: 10.1016/j.celrep.2016.06.086] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 05/31/2016] [Accepted: 06/22/2016] [Indexed: 12/13/2022] Open
Abstract
Deregulated cathepsin proteolysis occurs across numerous cancers, but in vivo substrates mediating tumorigenesis remain ill-defined. Applying 8-plex iTRAQ terminal amine isotopic labeling of substrates (TAILS), a systems-level N-terminome degradomics approach, we identified cathepsin B, H, L, S, and Z in vivo substrates and cleavage sites with the use of six different cathepsin knockout genotypes in the Rip1-Tag2 mouse model of pancreatic neuroendocrine tumorigenesis. Among 1,935 proteins and 1,114 N termini identified by TAILS, stable proteolytic products were identified in wild-type tumors compared with one or more different cathepsin knockouts (17%-44% of 139 cleavages). This suggests a lack of compensation at the substrate level by other cathepsins. The majority of neo-N termini (56%-83%) for all cathepsins was consistent with protein degradation. We validated substrates, including the glycolytic enzyme pyruvate kinase M2 associated with the Warburg effect, the ER chaperone GRP78, and the oncoprotein prothymosin-alpha. Thus, the identification of cathepsin substrates in tumorigenesis improves the understanding of cathepsin functions in normal physiology and cancer.
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26
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de Mingo Pulido A, Ruffell B. Immune Regulation of the Metastatic Process: Implications for Therapy. Adv Cancer Res 2016; 132:139-63. [PMID: 27613132 DOI: 10.1016/bs.acr.2016.05.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Metastatic disease is the major cause of fatalities in cancer patients, but few therapies are designed to target the metastatic process. Cancer cells must perform a number of steps to successfully establish metastatic foci, including local invasion, intravasation, survival, extravasation, and growth in ectopic tissue. Due to the nonrandom distribution of metastasis, it has long been recognized that the tissue microenvironment must be an important determinant of colonization. More recently it has been established in animal models that immune cells regulate the metastatic process, including a dominant role for monocytes and macrophages, and emerging roles for neutrophils and various lymphocyte populations. While most research has focused on the early dissemination process, patients usually present clinically with disseminated, if not macroscopic, disease. Identifying pathways by which immune cells regulate growth and therapeutic resistance within metastatic sites is therefore key to the development of pharmacological agents that will significantly extend patient survival.
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Affiliation(s)
- A de Mingo Pulido
- H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States
| | - B Ruffell
- H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States.
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27
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Abstract
In this study, Akkari et al. show the stage-dependent effects of simultaneously deleting cathepsin B (CtsB) and CtsS in a murine pancreatic neuroendocrine tumor model. They also identified CtsZ as the compensatory protease that regulates the acquired tumor-promoting functions of lesions deficient in both CtsB and CtsS, thus providing insight into a novel mechanism regulating tumorigenesis. Proteases are important for regulating multiple tumorigenic processes, including angiogenesis, tumor growth, and invasion. Elevated protease expression is associated with poor patient prognosis across numerous tumor types. Several multigene protease families have been implicated in cancer, including cysteine cathepsins. However, whether individual family members have unique roles or are functionally redundant remains poorly understood. Here we demonstrate stage-dependent effects of simultaneously deleting cathepsin B (CtsB) and CtsS in a murine pancreatic neuroendocrine tumor model. Early in tumorigenesis, the double knockout results in an additive reduction in angiogenic switching, whereas at late stages, several tumorigenic phenotypes are unexpectedly restored to wild-type levels. We identified CtsZ, which is predominantly supplied by tumor-associated macrophages, as the compensatory protease that regulates the acquired tumor-promoting functions of lesions deficient in both CtsB and CtsS. Thus, deletion of multiple cathepsins can lead to stage-dependent, compensatory mechanisms in the tumor microenvironment, which has potential implications for the clinical consideration of selective versus pan-family cathepsin inhibitors in cancer.
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28
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Strategies for detection and quantification of cysteine cathepsins-evolution from bench to bedside. Biochimie 2016; 122:48-61. [DOI: 10.1016/j.biochi.2015.07.029] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Accepted: 07/31/2015] [Indexed: 12/15/2022]
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29
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Yu R. Animal models of spontaneous pancreatic neuroendocrine tumors. Mol Cell Endocrinol 2016; 421:60-7. [PMID: 26261055 DOI: 10.1016/j.mce.2015.08.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Revised: 07/10/2015] [Accepted: 08/04/2015] [Indexed: 01/20/2023]
Abstract
Pancreatic neuroendocrine tumors (PNETs) are usually low-grade neoplasms derived from the endocrine pancreas. PNETs can be functioning and cause well-described hormonal hypersecretion syndromes or non-functioning and cause only tumor mass effect. PNETs appear to be more common recently likely due to incidental detection by imaging. Although the diagnosis and management of PNETs have been evolving rapidly, much remains to be studied in the areas of molecular pathogenesis, molecular markers of tumor behavior, early detection, and targeted drug therapy. Unique challenges facing PNETs studies are long disease course, the deep location of pancreas and difficult access to pancreatic tissue, and the variety of tumors, which make animal models valuable tools for PNETs studies. Existing animal models of PNETs have provided insights into the pathogenesis and natural history of human PNETs. Future studies on animal models of PNETs should address early tumor detection, molecular markers of tumor behavior, and novel targeted therapies.
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Affiliation(s)
- Run Yu
- Division of Endocrinology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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30
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Lysosomal cysteine peptidases – Molecules signaling tumor cell death and survival. Semin Cancer Biol 2015; 35:168-79. [DOI: 10.1016/j.semcancer.2015.08.001] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Revised: 07/31/2015] [Accepted: 08/03/2015] [Indexed: 12/18/2022]
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31
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Olson OC, Joyce JA. Cysteine cathepsin proteases: regulators of cancer progression and therapeutic response. Nat Rev Cancer 2015; 15:712-29. [PMID: 26597527 DOI: 10.1038/nrc4027] [Citation(s) in RCA: 469] [Impact Index Per Article: 46.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cysteine cathepsin protease activity is frequently dysregulated in the context of neoplastic transformation. Increased activity and aberrant localization of proteases within the tumour microenvironment have a potent role in driving cancer progression, proliferation, invasion and metastasis. Recent studies have also uncovered functions for cathepsins in the suppression of the response to therapeutic intervention in various malignancies. However, cathepsins can be either tumour promoting or tumour suppressive depending on the context, which emphasizes the importance of rigorous in vivo analyses to ascertain function. Here, we review the basic research and clinical findings that underlie the roles of cathepsins in cancer, and provide a roadmap for the rational integration of cathepsin-targeting agents into clinical treatment.
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Affiliation(s)
- Oakley C Olson
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
- Gerstner Sloan Kettering Graduate School of Biomedical Science, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA
| | - Johanna A Joyce
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
- Department of Oncology, University of Lausanne
- Ludwig Institute for Cancer Research, University of Lausanne, CH-1066 Lausanne, Switzerland
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32
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Thorsen SU, Sandahl K, Nielsen LB, Broe R, Rasmussen ML, Peto T, Grauslund J, Andersen MLM, Mortensen HB, Pociot F, Olsen BS, Brorsson C. Polymorphisms in the CTSH gene may influence the progression of diabetic retinopathy: a candidate-gene study in the Danish Cohort of Pediatric Diabetes 1987 (DCPD1987). Graefes Arch Clin Exp Ophthalmol 2015; 253:1959-65. [PMID: 26245339 DOI: 10.1007/s00417-015-3118-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Revised: 06/16/2015] [Accepted: 07/18/2015] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND The incidence of type 1 diabetes mellitus (T1DM) is increasing globally, and as a consequence, more patients are affected by microvascular complications such as diabetic retinopathy (DR). The aim of this study was to elucidate possible associations between diabetes-related single-nucleotide polymorphisms (SNP) and the development of DR. METHODS Three hundred and thirty-nine patients with T1DM from the Danish Cohort of Pediatric Diabetes 1987 (DCPD1987) went through an ophthalmic examination in 1995; 185 of these were reexamined in 2011. The development of DR was assessed by comparison of overall DR level between baseline and follow-up in the worst eye at baseline. Patients were graded on a modified version of the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, and 20 SNPs were genotyped in 130 of the 185 patients. RESULTS We found the CTSH/rs3825932 variant (C > T) was associated with reduced risk of progression to proliferative diabetic retinopathy (PDR) (OR [95 % CI] = 0.20 [0.07-0.56], p = 2.4 × 10(-3), padjust = 0.048) and ERBB3/rs2292239 variant (G > T) associated with increased risk of two-step progression (OR [95 % CI] = 2.76 [1.31-5.80], p = 7.5 × 10(-3), padjust = 0.15). The associations were independent of other known risk factors, such as HbA1c, sex, and diastolic blood pressure. CONCLUSION In conclusion, CTSH/rs3825932 and ERBB3/rs2292239 SNPs were associated with reduced risk of progression to PDR and two-step progression of DR on the ETDRS scale accordingly. The variant CTSH remained statistically significant after adjusting for multiple testing. Our results suggest an overlap between genetic variants that confer risk of T1DM and progression of DR.
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Affiliation(s)
- Steffen U Thorsen
- Department of Peadiatrics, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark
| | - Kristian Sandahl
- Department of Peadiatrics, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark.
| | - Lotte B Nielsen
- Department of Peadiatrics, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark
| | - Rebecca Broe
- Department of Ophthalmology, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark.,The Clinical Research Institute, University of Southern Denmark, Odense, Denmark.,OPEN Odense Patient data Explorative Network, Odense University Hospital, Odense, Denmark
| | - Malin L Rasmussen
- Department of Ophthalmology, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark.,The Clinical Research Institute, University of Southern Denmark, Odense, Denmark
| | - Tunde Peto
- The Clinical Research Institute, University of Southern Denmark, Odense, Denmark.,NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK
| | - Jakob Grauslund
- Department of Ophthalmology, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark.,The Clinical Research Institute, University of Southern Denmark, Odense, Denmark
| | - Marie L M Andersen
- Department of Peadiatrics, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark
| | - Henrik B Mortensen
- Department of Peadiatrics, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Flemming Pociot
- Department of Peadiatrics, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark
| | - Birthe S Olsen
- Department of Peadiatrics, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark
| | - Caroline Brorsson
- Department of Peadiatrics, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark
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Fan K, Li D, Zhang Y, Han C, Liang J, Hou C, Xiao H, Ikenaka K, Ma J. The induction of neuronal death by up-regulated microglial cathepsin H in LPS-induced neuroinflammation. J Neuroinflammation 2015; 12:54. [PMID: 25889123 PMCID: PMC4379721 DOI: 10.1186/s12974-015-0268-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2014] [Accepted: 02/17/2015] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Neuroinflammation is a hallmark that leads to selective neuronal loss and/or dysfunction in neurodegenerative disorders. Microglia-derived lysosomal cathepsins are increasingly recognized as important inflammatory mediators to trigger signaling pathways that aggravate neuroinflammation. However, cathepsin H (Cat H), a cysteine protease, has been far less studied in neuroinflammation, compared to cathepsins B, D, L, and S. The expression patterns and functional roles of Cat H in the brain in neuroinflammation remain unknown. METHODS C57BL/6J mice were intraperitoneally injected with either 0.9% saline or lipopolysaccharide (LPS, 5 mg/kg). Immunohistochemistry (IHC) and in situ hybridization (ISH) were used to analyze expression and localization of Cat H in the brain. Nitrite assay was used to examine microglial activation in vitro; ELISA was used to determine the release of Cat H and proinflammatory cytokines (TNF-α, IL-1β, IL-6, IFN-γ). Cat H activity was analyzed by cellular Cat H assay kit. Flow cytometry and in situ cell death detection were used to investigate neuronal death. Data were evaluated for statistical significance with one-way ANOVA and t test. RESULTS Cat H mRNA was only present in perivascular microglia and non-parenchymal sites under normal conditions. After LPS injection, Cat H mRNA expression in activated microglia in different brain regions was increased. Twenty-four hours after LPS injection, Cat H mRNA expression was maximal in SNr; 72 h later, it peaked in cerebral cortex and hippocampus then decreased and maintained at a low level. The expression of Cat H protein exhibited the similar alterations after LPS injection. In vitro, inflammatory stimulation (LPS, TNF-α, IL-1β, IL-6, and IFN-γ) increased the release and activity of Cat H in microglia. Conversely, addition of Cat H to microglia promoted the production and release of NO, IL-1β, and IFN-γ which could be prevented by neutralizing antibody. Further, addition of Cat H to Neuro2a cells induced neuronal death. CONCLUSIONS Taken together, these data indicate that the up-regulated microglial Cat H expression, release, and activity in the brain lead to neuronal death in neuroinflammation. The functional link of Cat H with microglial activation might contribute to the initiation and maintenance of microglia-driven chronic neuroinflammation.
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Affiliation(s)
- Kai Fan
- Department of Anatomy, Dalian Medical University, West Section No. 9, South Road, Lvshun, Dalian, 116044, , Liaoning, China.
| | - Daobo Li
- Clinical Medicine of Seven-year Education, Dalian Medical University, Dalian, 116044, , Liaoning, China.
| | - Yanli Zhang
- Department of Anatomy, Dalian Medical University, West Section No. 9, South Road, Lvshun, Dalian, 116044, , Liaoning, China.
| | - Chao Han
- Regenerative Medicine Center, the First Affiliated Hospital, Dalian Medical University, Dalian, 116011, , Liaoning, China.
| | - Junjie Liang
- Graduate School, Dalian Medical University, Dalian, 116044, , Liaoning, China.
| | - Changyi Hou
- Graduate School, Dalian Medical University, Dalian, 116044, , Liaoning, China.
| | - Hongliang Xiao
- Graduate School, Dalian Medical University, Dalian, 116044, , Liaoning, China.
| | - Kazuhiro Ikenaka
- Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki, 444-8787, , Aichi, Japan.
| | - Jianmei Ma
- Department of Anatomy, Dalian Medical University, West Section No. 9, South Road, Lvshun, Dalian, 116044, , Liaoning, China.
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Zhu W, Tao L, Quick ML, Joyce JA, Qu JM, Luo ZQ. Sensing cytosolic RpsL by macrophages induces lysosomal cell death and termination of bacterial infection. PLoS Pathog 2015; 11:e1004704. [PMID: 25738962 PMCID: PMC4349785 DOI: 10.1371/journal.ppat.1004704] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Accepted: 01/26/2015] [Indexed: 11/18/2022] Open
Abstract
The intracellular bacterial pathogen Legionella pneumophila provokes strong host responses and has proven to be a valuable model for the discovery of novel immunosurveillance pathways. Our previous work revealed that an environmental isolate of L. pneumophila induces a noncanonical form of cell death, leading to restriction of bacterial replication in primary mouse macrophages. Here we show that such restriction also occurs in infections with wild type clinical isolates. Importantly, we found that a lysine to arginine mutation at residue 88 (K88R) in the ribosome protein RpsL that not only confers bacterial resistance to streptomycin, but more importantly, severely attenuated the induction of host cell death and enabled L. pneumophila to replicate in primary mouse macrophages. Although conferring similar resistance to streptomycin, a K43N mutation in RpsL does not allow productive intracellular bacterial replication. Further analysis indicated that RpsL is capable of effectively inducing macrophage death via a pathway involved in lysosomal membrane permeabilization; the K88R mutant elicits similar responses but is less potent. Moreover, cathepsin B, a lysosomal protease that causes cell death after being released into the cytosol upon the loss of membrane integrity, is required for efficient RpsL-induced macrophage death. Furthermore, despite the critical role of cathepsin B in delaying RpsL-induced cell death, macrophages lacking cathepsin B do not support productive intracellular replication of L. pneumophila harboring wild type RpsL. This suggests the involvement of other yet unidentified components in the restriction of bacterial replication. Our results identified RpsL as a regulator in the interactions between bacteria such as L. pneumophila and primary mouse macrophages by triggering unique cellular pathways that restrict intracellular bacterial replication. The death of the host cell during infection can be triggered by one or more microbial molecules; this “live or die” selection provides effective means for the dissection of immune recognition mechanisms as well as for the identification of the microbial molecules responsible for such responses. We found that infection of primary mouse macrophages by Legionella pneumophila strains harboring wild type RpsL, the S12 component of the bacterial ribosome, causes macrophage death by a mechanism independent of the three inflammatory caspases, caspase 1, 7 and 11. Importantly, although both confer resistance to streptomycin at indistinguishable effectiveness, the K88R, but not the K43N mutation in RpsL enables L. pneumophila to replicate in macrophages. Purified RpsL and RpsLK43N physically delivered into macrophages cause cell death by inducing damage to lysosomal membranes and the release of cathepsins. We also found that the lysosomal protease cathepsin B is required for efficient RpsL-induced cell death but its absence is not sufficient for macrophages to support intracellular bacterial replication. Thus, RpsL functions as an immune induction molecule to trigger one or more signaling cascades that leads to lysosomal cell death as well as the termination of bacterial replication.
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Affiliation(s)
- Wenhan Zhu
- Department of Biological Sciences, Purdue University, West Lafayette, Indiana, United States of America
| | - Lili Tao
- Department of Biological Sciences, Purdue University, West Lafayette, Indiana, United States of America
- Department of Pulmonary Medicine, Huadong Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Marsha L. Quick
- Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
| | - Johanna A. Joyce
- Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America
| | - Jie-Ming Qu
- Department of Pulmonary Medicine, Huadong Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Zhao-Qing Luo
- Department of Biological Sciences, Purdue University, West Lafayette, Indiana, United States of America
- * E-mail:
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Singh M, Raghav N. 2,3-Dihydroquinazolin-4(1H)-one derivatives as potential non-peptidyl inhibitors of cathepsins B and H. Bioorg Chem 2015; 59:12-22. [PMID: 25665518 DOI: 10.1016/j.bioorg.2015.01.005] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2014] [Revised: 01/15/2015] [Accepted: 01/19/2015] [Indexed: 12/17/2022]
Abstract
A direct correlation between cathepsin expression-cancer progression and elevated levels of cathepsins due to an imbalance in cellular inhibitors-cathepsins ratio in inflammatory diseases necessitates the work on the identification of potential inhibitors to cathepsins. In the present work we report the synthesis of some 2,3-dihydroquinazolin-4(1H)-ones followed by their evaluation as cysteine protease inhibitors in general and cathepsin B and cathepsin H inhibitors in particular. 2,3-Dihydroquinazolin-4(1H)-ones, synthesized by the condensation of anthranilamide and carbonyl compound in presence of PPA-SiO2 catalyst, were characterized by spectral analysis. The designed compounds were screened as inhibitors to proteolysis on endogenous protein substrates. Further, a distinct differential pattern of inhibition was obtained for cathepsins B and H. The inhibition was more to cathepsin B with Ki values in nanomolar range. However, cathepsin H was inhibited at micromolar concentration. Maximum inhibition was shown by compounds, 1e and 1f for cathepsin B and compounds 1c and 1f for cathepsin H. The synthesized compounds were established as reversible inhibitors of cathepsins B and H. The results were also compared with the energy of interaction between enzyme active site and compounds using iGemdock software.
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Affiliation(s)
- Mamta Singh
- Department of Chemistry, Kurukshetra University, Kurukshetra 136119, India
| | - Neera Raghav
- Department of Chemistry, Kurukshetra University, Kurukshetra 136119, India.
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36
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Ravish I, Raghav N. SAR studies of differently functionalized 4′-phenylchalcone based compounds as inhibitors of cathepsins B, H and L. RSC Adv 2015. [DOI: 10.1039/c5ra00357a] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
4′-Phenylchalcones and their cyclised derivatives as novel inhibitors of cathepsin B, H and L, potential anticancer agents.
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Affiliation(s)
- Indu Ravish
- Department of Chemistry
- Kurukshetra University
- Kurukshetra-136119
- India
| | - Neera Raghav
- Department of Chemistry
- Kurukshetra University
- Kurukshetra-136119
- India
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37
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Akkari L, Gocheva V, Kester JC, Hunter KE, Quick ML, Sevenich L, Wang HW, Peters C, Tang LH, Klimstra DS, Reinheckel T, Joyce JA. Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix. Genes Dev 2014; 28:2134-50. [PMID: 25274726 PMCID: PMC4180975 DOI: 10.1101/gad.249599.114] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
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.
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Affiliation(s)
- Leila Akkari
- Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York,10065, USA
| | - Vasilena Gocheva
- Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York,10065, USA
| | - Jemila C Kester
- Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York,10065, USA
| | - Karen E Hunter
- Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York,10065, USA
| | - Marsha L Quick
- Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York,10065, USA
| | - Lisa Sevenich
- Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York,10065, USA
| | - Hao-Wei Wang
- Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York,10065, USA
| | - Christoph Peters
- Institute of Molecular Medicine and Cell Research, Albert-Ludwigs University, D-79104 Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, D-79104 Freiburg, Germany; German Cancer Consortium (DKTK), D-79104 Freiburg, Germany
| | - Laura H Tang
- Pathology Department, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA
| | - David S Klimstra
- Pathology Department, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA
| | - Thomas Reinheckel
- Institute of Molecular Medicine and Cell Research, Albert-Ludwigs University, D-79104 Freiburg, Germany; BIOSS Centre for Biological Signalling Studies, D-79104 Freiburg, Germany; German Cancer Consortium (DKTK), D-79104 Freiburg, Germany
| | - Johanna A Joyce
- Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York,10065, USA;
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CTSH regulates β-cell function and disease progression in newly diagnosed type 1 diabetes patients. Proc Natl Acad Sci U S A 2014; 111:10305-10. [PMID: 24982147 DOI: 10.1073/pnas.1402571111] [Citation(s) in RCA: 82] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Over 40 susceptibility loci have been identified for type 1 diabetes (T1D). Little is known about how these variants modify disease risk and progression. Here, we combined in vitro and in vivo experiments with clinical studies to determine how genetic variation of the candidate gene cathepsin H (CTSH) affects disease mechanisms and progression in T1D. The T allele of rs3825932 was associated with lower CTSH expression in human lymphoblastoid cell lines and pancreatic tissue. Proinflammatory cytokines decreased the expression of CTSH in human islets and primary rat β-cells, and overexpression of CTSH protected insulin-secreting cells against cytokine-induced apoptosis. Mechanistic studies indicated that CTSH exerts its antiapoptotic effects through decreased JNK and p38 signaling and reduced expression of the proapoptotic factors Bim, DP5, and c-Myc. CTSH overexpression also up-regulated Ins2 expression and increased insulin secretion. Additionally, islets from Ctsh(-/-) mice contained less insulin than islets from WT mice. Importantly, the TT genotype was associated with higher daily insulin dose and faster disease progression in newly diagnosed T1D patients, indicating agreement between the experimental and clinical data. In line with these observations, healthy human subjects carrying the T allele have lower β-cell function, which was evaluated by glucose tolerance testing. The data provide strong evidence that CTSH is an important regulator of β-cell function during progression of T1D and reinforce the concept that candidate genes for T1D may affect disease progression by modulating survival and function of pancreatic β-cells, the target cells of the autoimmune assault.
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Raghav N, Singh M. Design, synthesis and docking studies of bischalcones based quinazoline-2(1H)-ones and quinazoline-2(1H)-thiones derivatives as novel inhibitors of cathepsin B and cathepsin H. Eur J Pharm Sci 2014; 54:28-39. [DOI: 10.1016/j.ejps.2013.12.018] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Revised: 12/03/2013] [Accepted: 12/29/2013] [Indexed: 11/30/2022]
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Fonović M, Turk B. Cysteine cathepsins and extracellular matrix degradation. Biochim Biophys Acta Gen Subj 2014; 1840:2560-70. [PMID: 24680817 DOI: 10.1016/j.bbagen.2014.03.017] [Citation(s) in RCA: 243] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Revised: 03/16/2014] [Accepted: 03/22/2014] [Indexed: 01/03/2023]
Abstract
BACKGROUND Cysteine cathepsins are normally found in the lysosomes where they are involved in intracellular protein turnover. Their ability to degrade the components of the extracellular matrix in vitro was first reported more than 25years ago. However, cathepsins were for a long time not considered to be among the major players in ECM degradation in vivo. During the last decade it has, however, become evident that abundant secretion of cysteine cathepsins into extracellular milieu is accompanying numerous physiological and disease conditions, enabling the cathepsins to degrade extracellular proteins. SCOPE OF VIEW In this review we will focus on cysteine cathepsins and their extracellular functions linked with ECM degradation, including regulation of their activity, which is often enhanced by acidification of the extracellular microenvironment, such as found in the bone resorption lacunae or tumor microenvironment. We will further discuss the ECM substrates of cathepsins with a focus on collagen and elastin, including the importance of that for pathologies. Finally, we will overview the current status of cathepsin inhibitors in clinical development for treatment of ECM-linked diseases, in particular osteoporosis. MAJOR CONCLUSIONS Cysteine cathepsins are among the major proteases involved in ECM remodeling, and their role is not limited to degradation only. Deregulation of their activity is linked with numerous ECM-linked diseases and they are now validated targets in a number of them. Cathepsins S and K are the most attractive targets, especially cathepsin K as a major therapeutic target for osteoporosis with drugs targeting it in advanced clinical trials. GENERAL SIGNIFICANCE Due to their major role in ECM remodeling cysteine cathepsins have emerged as an important group of therapeutic targets for a number of ECM-related diseases, including, osteoporosis, cancer and cardiovascular diseases. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.
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Affiliation(s)
- Marko Fonović
- Department of Biochemistry, Molecular and Structural Biology, Jozef Stefan Institute, Jamova cesta 39, SI-1000 Ljubljana, Slovenia; Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins, Jamova cesta 39, SI-1000 Ljubljana, Slovenia.
| | - Boris Turk
- Department of Biochemistry, Molecular and Structural Biology, Jozef Stefan Institute, Jamova cesta 39, SI-1000 Ljubljana, Slovenia; Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins, Jamova cesta 39, SI-1000 Ljubljana, Slovenia; Faculty of Chemistry and Chemical Technology, University of Ljubljana, Slovenia.
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Tan GJ, Peng ZK, Lu JP, Tang FQ. Cathepsins mediate tumor metastasis. World J Biol Chem 2013; 4:91-101. [PMID: 24340132 PMCID: PMC3856311 DOI: 10.4331/wjbc.v4.i4.91] [Citation(s) in RCA: 142] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2013] [Revised: 09/06/2013] [Accepted: 09/17/2013] [Indexed: 02/05/2023] Open
Abstract
Cathepsins are highly expressed in various human cancers, associated with tumor metastasis. It is superfamily, concluding A, B, C, D, E, F, G, H, L, K, O, S, V, and W family members. As a group of lysosomal proteinases or endopeptidases, each member has a different function, playing different roles in distinct tumorigenic processes such as proliferation, angiogenesis, metastasis, and invasion. Cathepsins belong to a diverse number of enzyme subtypes, including cysteine proteases, serine proteases and aspartic proteases. The contribution of cathepsins to invasion in human cancers is well documented, although the precise mechanisms by which cathepsins exert their effects are still not clear. In the present review, the role of cathepsin family members in cancer is discussed.
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Aldahmesh M, Khan A, Alkuraya H, Adly N, Anazi S, Al-Saleh A, Mohamed J, Hijazi H, Prabakaran S, Tacke M, Al-Khrashi A, Hashem M, Reinheckel T, Assiri A, Alkuraya F. Mutations in LRPAP1 are associated with severe myopia in humans. Am J Hum Genet 2013; 93:313-20. [PMID: 23830514 DOI: 10.1016/j.ajhg.2013.06.002] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2013] [Revised: 05/30/2013] [Accepted: 06/03/2013] [Indexed: 10/26/2022] Open
Abstract
Myopia is an extremely common eye disorder but the pathogenesis of its isolated form, which accounts for the overwhelming majority of cases, remains poorly understood. There is strong evidence for genetic predisposition to myopia, but determining myopia genetic risk factors has been difficult to achieve. We have identified Mendelian forms of myopia in four consanguineous families and implemented exome/autozygome analysis to identify homozygous truncating variants in LRPAP1 and CTSH as the likely causal mutations. LRPAP1 encodes a chaperone of LRP1, which is known to influence TGF-β activity. Interestingly, we observed marked deficiency of LRP1 and upregulation of TGF-β in cells from affected individuals, the latter being consistent with available data on the role of TGF-β in the remodeling of the sclera in myopia and the high frequency of myopia in individuals with Marfan syndrome who characteristically have upregulation of TGF-β signaling. CTSH, on the other hand, encodes a protease and we show that deficiency of the murine ortholog results in markedly abnormal globes consistent with the observed human phenotype. Our data highlight a role for LRPAP1 and CTSH in myopia genetics and demonstrate the power of Mendelian forms in illuminating new molecular mechanisms that may be relevant to common phenotypes.
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Abstract
Pancreatic neuroendocrine tumors (PNETs), also known as islet cell tumors, are mostly indolent neoplasms that probably arise from a network of endocrine cells that includes islet cells and pluripotent precursors in the pancreatic ductal epithelium. The incidence and prevalence of PNETs continue to rise in recent years because of more sensitive detection. The molecular pathogenesis, early detection, molecular predictors of tumor behavior, and targeted drug therapy of PNETs are not well understood and require additional basic and translational research. The rarity and indolent nature of these tumors, difficulty of access to appropriate patient tissue samples, and varying histopathology and secreted hormones pose particular challenges to PNET researchers. Animal models and cell lines are indispensable tools for investigating the pathogenesis, pathophysiology, mechanisms for tumor invasion and metastasis, and therapeutics of PNETs. This review summarizes currently available animal models and cell lines of PNETs, which have provided valuable insights into the pathogenesis and natural history of human PNETs. In the future, animal models and cell lines of PNETs should also be used to study early tumor detection and molecular predictors of tumor behavior and to test the responses to, and mechanisms for, novel targeted drug therapies.
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Coto-Montes A, García-Macía M, Caballero B, Sierra V, Rodríguez-Colunga MJ, Reiter RJ, Vega-Naredo I. Analysis of constant tissue remodeling in Syrian hamster Harderian gland: intra-tubular and inter-tubular syncytial masses. J Anat 2013; 222:558-69. [PMID: 23496762 PMCID: PMC3633345 DOI: 10.1111/joa.12040] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/25/2013] [Indexed: 01/26/2023] Open
Abstract
The Syrian hamster Harderian gland (HG) has a marked sexual dimorphism and exhibits an extraordinary rate of porphyrinogenesis. The physiological oxidative stress, derived from constant porphyrin production, is so high that the HG needs additional survival autophagic mechanisms to fight against this chronic exposure, provoking the triggering of a holocrine secretion in female glands that forms two types of secretory masses: intra-tubular-syncytial and inter-tubular-syncytial masses. The aim of this work was to study the development of this inter-tubular holocrine secretion. To approach this task, we have considered that the steps developed during the formation of the so-called invasive masses consist of the growth of epithelial cells, cell detachment from the basal lamina and invasion of surrounding tissues. The presence of these masses, particularly in the female HG, are closely linked to sexual dimorphism in redox balance and to alterations in the expression of certain factors such as cytokeratins, P-cadherin, matrix metalloproteinases, cathepsin H, proliferating cell nuclear antigen, p53, CD-31 and vascular endothelial growth factor, which seem to be involved in tissue remodeling. The results document unusual mechanisms of secretion in Syrian hamster HG: an extraordinary system of massive secretion through the conjunctive tissue, disrupting the branched structure of the gland.
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Affiliation(s)
- Ana Coto-Montes
- Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain
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Kallunki T, Olsen OD, Jäättelä M. Cancer-associated lysosomal changes: friends or foes? Oncogene 2013; 32:1995-2004. [PMID: 22777359 DOI: 10.1038/onc.2012.292] [Citation(s) in RCA: 224] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2012] [Accepted: 06/01/2012] [Indexed: 12/28/2022]
Abstract
Rapidly dividing and invasive cancer cells are strongly dependent on effective lysosomal function. Accordingly, transformation and cancer progression are characterized by dramatic changes in lysosomal volume, composition and cellular distribution. Depending on one's point of view, the cancer-associated changes in the lysosomal compartment can be regarded as friends or foes. Most of them are clearly transforming as they promote invasive growth, angiogenesis and drug resistance. The same changes can, however, strongly sensitize cells to lysosomal membrane permeabilization and thereby to lysosome-targeting anti-cancer drugs. In this review we compile our current knowledge on cancer-associated changes in lysosomal composition and discuss the consequences of these alterations to cancer progression and the possibilities they can bring to cancer therapy.
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Affiliation(s)
- T Kallunki
- Cell Death and Metabolism and Centre for Genotoxic Stress Research, Danish Cancer Society Research Center, Copenhagen, Denmark
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Kachgal S, Carrion B, Janson IA, Putnam AJ. Bone marrow stromal cells stimulate an angiogenic program that requires endothelial MT1-MMP. J Cell Physiol 2012; 227:3546-55. [PMID: 22262018 DOI: 10.1002/jcp.24056] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Bone marrow-derived stromal/stem cells (BMSCs) have recently been characterized as mediators of tissue regeneration after injury. In addition to preventing fibrosis at the wound site, BMSCs elicit an angiogenic response within the fibrin matrix. The mechanistic interactions between BMSCs and invading endothelial cells (ECs) during this process are not fully understood. Using a three-dimensional, fibrin-based angiogenesis model, we sought to investigate the proteolytic mechanisms by which BMSCs promote vessel morphogenesis. We find that BMSC-mediated vessel formation depends on the proteolytic ability of membrane type 1-matrix metalloproteinase (MT1-MMP). Knockdown of the protease results in a small network of vessels with enlarged lumens. Contrastingly, vessel morphogenesis is unaffected by the knockdown of MMP-2 and MMP-9. Furthermore, we find that BMSC-mediated vessel morphogenesis in vivo follows mechanisms similar to what we observe in vitro. Subcutaneous, cellular fibrin implants in C.B-17/SCID mice form aberrant vasculature when MMPs are inhibited with a broad-spectrum chemical inhibitor, and a very minimal amount of vessels when MT1-MMP proteolytic activity is interrupted in ECs. Other studies have debated the necessity of MT1-MMP in the context of vessel invasion in fibrin, but this study clearly demonstrates its requirement in BMSC-mediated angiogenesis.
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Affiliation(s)
- Suraj Kachgal
- Department of Biomedical Engineering, University of California, Irvine, Irvine, CA, USA
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Lu WD, Funkelstein L, Toneff T, Reinheckel T, Peters C, Hook V. Cathepsin H functions as an aminopeptidase in secretory vesicles for production of enkephalin and galanin peptide neurotransmitters. J Neurochem 2012; 122:512-22. [PMID: 22582844 PMCID: PMC3417130 DOI: 10.1111/j.1471-4159.2012.07788.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Peptide neurotransmitters function as key intercellular signaling molecules in the nervous system. These peptides are generated in secretory vesicles from proneuropeptides by proteolytic processing at dibasic residues, followed by removal of N- and/or C-terminal basic residues to form active peptides. Enkephalin biosynthesis from proenkephalin utilizes the cysteine protease cathepsin L and the subtilisin-like prohormone convertase 2 (PC2). Cathepsin L generates peptide intermediates with N-terminal basic residue extensions, which must be removed by an aminopeptidase. In this study, we identified cathepsin H as an aminopeptidase in secretory vesicles that produces (Met)enkephalin (ME) by sequential removal of basic residues from KR-ME and KK-ME, supported by in vivo knockout of the cathepsin H gene. Localization of cathepsin H in secretory vesicles was demonstrated by immunoelectron microscopy and immunofluorescence deconvolution microscopy. Purified human cathepsin H sequentially removes N-terminal basic residues to generate ME, with peptide products characterized by nano-LC-MS/MS tandem mass spectrometry. Cathepsin H shows highest activities for cleaving N-terminal basic residues (Arg and Lys) among amino acid fluorogenic substrates. Notably, knockout of the cathepsin H gene results in reduction of ME in mouse brain. Cathepsin H deficient mice also show a substantial decrease in galanin peptide neurotransmitter levels in brain. These results illustrate a role for cathepsin H as an aminopeptidase for enkephalin and galanin peptide neurotransmitter production.
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Affiliation(s)
- Weiya Douglas Lu
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA, USA
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Cathepsins and pancreatic cancer: the 2012 update. Pancreatology 2012; 12:395-401. [PMID: 23127526 DOI: 10.1016/j.pan.2012.07.011] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2012] [Revised: 07/06/2012] [Accepted: 07/10/2012] [Indexed: 02/06/2023]
Abstract
Pancreatic cancer is the result of distinctive genetic and epigenetic disturbances. This multistep process is in part well-defined and includes alterations in oncogenes and suppressor genes that control proliferation, apoptosis, angiogenesis, invasion and cell migration. Cathepsins are proteolytic enzymes and represent potential therapeutic targets in human tumors. Cathepsins predominantly function as endopeptidases within endolysosomal vesicles of normal cells and they are involved in physiological processes such as protein turnover, differentiation and apoptosis. In various types of malignancies, cathepsins have been associated with tumor progression and metastasis. Growing evidence and direct proofs suggest that cathepsins are highly up-regulated in pancreatic cancer and contribute to the development and progression of the cancer phenotype. In this review, the role of cathepsins in pancreatic cancer tumorigenesis is reported and discussed. Some critical aspects will be underlined such as specificity of cathepsin activity in pancreatic cancer and in its precursor lesions; the genetic perturbation and the intracellular signaling pathway activated by cathepsins as reported in preclinical models and in human tissues; the preliminary results and the oncological effects of cathepsin inhibitors currently tested on pancreatic cancer cells; the role of combined therapy based on chemotherapeutic agents and cathepsin inhibition. Although mounting evidences indicate that cysteine cathepsins are potential therapeutic targets in pancreatic cancer, as suggested by their functional role in controlling invasiveness and metastasis, it remains to be seen whether the promising benefits of pharmacological inhibitors observed in preclinical study might be translated to the current clinical practice.
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Reinheckel T, Peters C, Krüger A, Turk B, Vasiljeva O. Differential Impact of Cysteine Cathepsins on Genetic Mouse Models of De novo Carcinogenesis: Cathepsin B as Emerging Therapeutic Target. Front Pharmacol 2012; 3:133. [PMID: 22798952 PMCID: PMC3394080 DOI: 10.3389/fphar.2012.00133] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2012] [Accepted: 06/24/2012] [Indexed: 12/12/2022] Open
Abstract
Lysosomal cysteine cathepsins belong to a family of 11 human proteolytic enzymes. Some of them correlate with progression in a variety of cancers and therefore are considered as potential therapeutic targets. Until recently, the contribution of individual cathepsins to tumorigenesis and tumor progression remained unknown. By crossing various types of mouse cancer models with mice where specific cathepsins have been ablated, we contributed to this gap of knowledge and will summarize the results in this report. The employed models are the Rip1-Tag2 model for pancreatic neuroendocrine tumors, the K14-HPV16 model for squamous skin and cervical cancers, and the MMTV-PyMT model for metastasizing breast cancer, the KPC model for pancreatic ductal adenocarcinoma, and the APC(min) mice developing early stages of intestinal neoplasia. All models harbor mutations in relevant tumor suppressors and/or cell-type specific expression of potent oncogenes, which initiate de novo carcinogenesis in the targeted tissues. In all these models deletion of cathepsin B led to suppression of the aggressiveness of the respective cancer phenotype. Cathepsin B is networking with other proteases as it was shown for cathepsin X/Z. In contrast, deletion of cathepsin L was beneficial in the RiP1-Tag2 model, but enhanced tumorigenesis in the APC(min), and the K14-HPV16 mice. A logical consequence of these results would be to further pursue selective inhibition of cathepsin B. Moreover, it became clear that cathepsins B and S derived from cells of the tumor microenvironment support cancer growth. Strikingly, delivery of broad spectrum cysteine cathepsin inhibitors in the tumor microenvironment disrupts the permissive ecosystem of the cancer and results in impaired growth or even in regression of the tumor. In addition, combination of cysteine cathepsin inhibition and standard chemotherapy improves the therapeutic response of the latter. Taken together, the next preclinical challenges for developing cathepsin inhibition as cancer therapy might be the improvement of inhibitor selectivity and targeted delivery to the tumor microenvironment and investigation of the biological context of the individual factors within the complex proteolytic network.
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Affiliation(s)
- Thomas Reinheckel
- Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg Freiburg, Germany
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Rojnik M, Jevnikar ZR, Doljak B, Turk S, Zidar N, Kos J. The influence of differential processing of procathepsin H on its aminopeptidase activity, secretion and subcellular localization in human cell lines. Eur J Cell Biol 2012; 91:757-64. [PMID: 22704610 DOI: 10.1016/j.ejcb.2012.05.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2012] [Revised: 04/25/2012] [Accepted: 05/10/2012] [Indexed: 10/28/2022] Open
Abstract
Cathepsin H is a unique member of the cysteine cathepsins that acts primarily as an aminopeptidase. Like other cysteine cathepsins, it is synthesized as an inactive precursor and activated by proteolytic removal of its propeptide. Here we demonstrate that, in human cells, the processing of the propeptide is an autocatalytic, multistep process proceeding from an inactive 41kDa pro-form, through a 30kDa intermediate form, to the 28kDa mature form. Tyr87P and Gly90P were identified as the two major endopeptidase cleavage sites, converting the 30kDa form into the mature 28kDa form. The level of processing differs significantly in different human cell lines. In monocyte-derived macrophages U937 and prostate cancer cells PC-3, the 28kDa form is predominant, whereas in osteoblasts HOS the processing from the 30kDa form to the 28kDa form is significantly lower. The aminopeptidase activity of the enzyme and its subcellular localization are independent of the product, however the 30kDa form was not secreted in HOS cells. The activity of the resulting cathepsin H in U937 cells was significantly lower than that in HOS cells, presumably due to the high levels of endogenous cysteine protease inhibitor cystatin F present specifically in this cell line. These results provide an insight into the dependence of human cathepsin H processing and regulation on cell type.
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Affiliation(s)
- Matija Rojnik
- Department of Pharmaceutical Biology, University of Ljubljana, Ljubljana, Slovenia
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