Cancer nanomedicine using nanoparticle-based delivery systems has shown outstanding promise in recent decades for improving anticancer treatment. However, limited targeting efficiency, low drug ...loading efficiency and innate toxicity of nanoparticles have caused severe problems, leaving only a few available in the clinic. Here, we newly developed carrier-free nanoparticles of cathepsin B-cleavable peptide (Phe-Arg-Arg-Gly; FRRG)-conjugated doxorubicin (DOX) prodrug (FRRG-DOX) that formed a stable nanoparticle structure with an average diameter of 213 nm in aqueous condition. The carrier-free nanoparticles of FRRG-DOX induced cytotoxicity against cathepsin B-overexpressed tumor cells whereas the toxicity was minimized in normal cells. In particular, the FRRG-DOX nanoparticles showed the successful tumor-targeting ability and enhanced therapeutic efficiency in human colon adenocarcinoma (HT-29) tumor-bearing mice via enhanced permeation and retention (EPR) effect. Furthermore, FRRG-DOX nanoparticles did not present any severe toxicity, such as non-specific cell death and cardiac toxicity, in normal tissues due to minimal expression of cathepsin B. This carrier-free nanoparticles of FRRG-DOX can solve the unavoidable problems of current nanomedicine, such as lower targeting efficiency, toxicity of nanoparticles themselves, and difficulty in mass production that are fatally caused by natural and synthetic nano-sized carriers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Peripheral processes that mediate beneficial effects of exercise on the brain remain sparsely explored. Here, we show that a muscle secretory factor, cathepsin B (CTSB) protein, is important for the ...cognitive and neurogenic benefits of running. Proteomic analysis revealed elevated levels of CTSB in conditioned medium derived from skeletal muscle cell cultures treated with AMP-kinase agonist AICAR. Consistently, running increased CTSB levels in mouse gastrocnemius muscle and plasma. Furthermore, recombinant CTSB application enhanced expression of brain-derived neurotrophic factor (BDNF) and doublecortin (DCX) in adult hippocampal progenitor cells through a mechanism dependent on the multifunctional protein P11. In vivo, in CTSB knockout (KO) mice, running did not enhance adult hippocampal neurogenesis and spatial memory function. Interestingly, in Rhesus monkeys and humans, treadmill exercise elevated CTSB in plasma. In humans, changes in CTSB levels correlated with fitness and hippocampus-dependent memory function. Our findings suggest CTSB as a mediator of effects of exercise on cognition.
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•Proteomics of AICAR-treated L6 muscle cells reveals myokine cathepsin B (CTSB)•Exercise increases CTSB levels in mouse, monkey, and human plasma•Running does not improve memory or adult neurogenesis in CTSB knockout mice•CTSB enhances neurotrophin levels in adult hippocampal progenitor cells•In humans, plasma CTSB levels are positively correlated with fitness and memory
Moon et al. show that cathepsin B (CTSB), an exercise myokine, has beneficial effects on cognition such as enhanced adult hippocampal neurogenesis and spatial memory in mice. Treadmill exercise elevated plasma CTSB in monkeys and humans. In humans, CTSB levels correlated with fitness and hippocampus-dependent memory function.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Until recently, chemiluminescence cell images could only be obtained using luciferase‐activated probes. Moreover, chemiluminescence microscopy cell‐imaging has not been demonstrated for natively ...expressed enzymes like cathepsin B. Herein, we describe the design, synthesis, and evaluation of the first chemiluminescence probe for the detection and imaging of cathepsin B. The probe activation mechanism relies on the release of a dioxetane intermediate, which undergoes chemiexcitation to emit green light with high efficiency under physiological conditions. Using the probe, we obtained clear images of cancerous leukemia and colon cells. This is the first demonstration of chemiluminescence cell images obtained by a probe for a natively expressed endogenous enzyme. We anticipate that the concept presented in this study will be broadly used to develop analogous probes for other important proteases relevant to biomolecular processes.
Chemiluminescence cell‐imaging: The first chemiluminescence probe for the detection of cathepsin B is described. The probe showed unprecedented sensitivity compared to that of a classic fluorescent probe for cathepsin B and provided the first chemiluminescence microscopy cell images of a natively expressed enzyme, thereby enabling differentiation between cancerous cells and normal tissue.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
4.
Cathepsin B as a cancer target Gondi, Christopher S; Rao, Jasti S
Expert opinion on therapeutic targets,
03/2013, Volume:
17, Issue:
3
Journal Article
Peer reviewed
Open access
Introduction:
Cathepsin B is of significant importance to cancer therapy as it is involved in various pathologies and oncogenic processes in humans. Numerous studies have shown that abnormal ...regulation of cathepsin B overexpression is correlated with invasive and metastatic phenotypes in cancers. Cathepsin B is normally associated with the lysosomes involved in autophagy and immune response, but its aberrant expression has been shown to lead to cancers.
Areas covered:
This review highlights the oncogenic role of cathepsin B, discusses the regulation of cathepsin B in light of oncogenesis, discusses the role of cathepsin B as a signaling molecule, and highlights the therapeutic potential of targeting cathepsin B.
Expert opinion:
Targeting cathepsin B alone does not appear to abolish tumor growth, and this is probably because cathepsin B appears to have diverse functions and influence numerous pathways. It is not clear whether global suppression of cathepsin B activity or expression would produce unintended effects or cause the activation or suppression of unwanted pathways. A localized approach for targeting the expression of cathepsin B would be more relevant. Moreover, a combination of targeting cathepsin B with other relevant oncogenic molecules has significant therapeutic potential.
Clinical, biochemical and molecular biology studies have identified lysosome-encapsulated cellular proteases as critical risk factors for cancer progression. Cathepsins represent a group of such ...proteases aimed at maintenance of cellular homeostasis. Nevertheless, recent reports suggest that Cathepsin B executes other cellular programs such as controlling tumor growth, migration, invasion, angiogenesis, and metastases development. In fact, elevated levels of Cathepsins are found under different pathological conditions including inflammation, infection, neurodegenerative disease, and cancer. Furthermore, the discovery of Cathepsin B secretion and function as an extracellular matrix protein has broadened our appreciation for the impact of Cathepsin B on cancer progression. Underneath a façade of an intracellular protease with limited therapeutic potential hides a central role of cathepsins in extracellular functions. Moreover, this role is incredibly diverse from one condition to the next – from driving caspase-dependent apoptosis to facilitating tumor neovascularization and metastasis. Here we discuss the role of Cathepsin B in the oncogenic process and perspective the use of Cathepsin B for diagnostic and therapeutic applications.
•Cathepsins represent a group of cysteine proteases.•Cathepsins maintain homeostais in normal and pathological states of the cell.•Cathepsin B role in anticancer therapy is diverse.•Modulation of Cathepsin B regulates autophagy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Investigations of Alzheimer's disease (AD), traumatic brain injury (TBI), and related brain disorders have provided extensive evidence for involvement of cathepsin B, a lysosomal cysteine protease, ...in mediating the behavioral deficits and neuropathology of these neurodegenerative diseases. This review integrates findings of cathepsin B regulation in clinical biomarker studies, animal model genetic and inhibitor evaluations, structural studies, and lysosomal cell biological mechanisms in AD, TBI, and related brain disorders. The results together indicate the role of cathepsin B in the behavioral deficits and neuropathology of these disorders. Lysosomal leakage occurs in AD and TBI, and related neurodegeneration, which leads to the hypothesis that cathepsin B is redistributed from the lysosome to the cytosol where it initiates cell death and inflammation processes associated with neurodegeneration. These results together implicate cathepsin B as a major contributor to these neuropathological changes and behavioral deficits. These findings support the investigation of cathepsin B as a potential drug target for therapeutic discovery and treatment of AD, TBI, and TBI-related brain disorders.
•Cathepsin B is elevated in human Alzheimer's disease (AD) and traumatic brain injury (TBI) patients, and correlates with behavioral and injury outcomes•Inhibition of cathepsin B in AD and TBI animal models results in alleviation of cognitive and behavioral deficits with improvement in neuropathology•Preprocathepsin B undergoes processing to generate mature cathepsin B, which can be selectively inhibited by CA-074•The occluding loop of cathepsin B regulates dipeptidylcarboxypeptidase and endopeptidase activities of cathepsin B•Lysosomal leakage of cathepsin B to the cytosol participates in cell death and inflammation of AD, TBI, and related brain disorders
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Lysosomes are membrane-surrounded cytoplasmic organelles filled with a powerful cocktail of hydrolases. Besides degrading cellular constituents inside the lysosomal lumen, lysosomal hydrolases ...promote tissue remodeling when delivered to the extracellular space and cell death when released to the cytosol. Here, we show that spatially and temporally controlled lysosomal leakage contributes to the accurate chromosome segregation in normal mammalian cell division. One or more chromatin-proximal lysosomes leak in the majority of prometaphases, after which active cathepsin B (CTSB) localizes to the metaphase chromatin and cleaves a small subset of histone H3. Stabilization of lysosomal membranes or inhibition of CTSB activity during mitotic entry results in a significant increase in telomere-related chromosome segregation defects, whereas cells and tissues lacking CTSB and cells expressing CTSB-resistant histone H3 accumulate micronuclei and other nuclear defects. These data suggest that lysosomal leakage and chromatin-associated CTSB contribute to proper chromosome segregation and maintenance of genomic integrity.
•A clickable and tagless activity-based probe (ABP) of human cathepsin B, KDA-1, is developed with a minimalistic design approach for enhanced selectivity.•The probe KDA-1 is highly selective, and ...targets the active site Cys29 residue for labeling in an activity-dependent manner.•A cell permeable analogue, KDA-1-OMe has also been developed and characterized.•Cathepsin B probe, KDA-1, can successfully label the active enzyme from proteomes derived from human MDA-MB-231 breast cancer cells and HEK293 cells.
Human cathepsin B is a cysteine-dependent protease whose roles in both normal and diseased cellular states remain yet to be fully delineated. This is primarily due to overlapping substrate specificities and lack of unambiguously annotated physiological functions. In this work, a selective, cell-permeable, clickable and tagless small molecule cathepsin B probe, KDA-1, is developed and kinetically characterized. KDA-1 selectively targets active site Cys25 residue of cathepsin B for labeling and can detect active cellular cathepsin B in proteomes derived from live human MDA-MB-231 breast cancer cells and HEK293 cells. It is anticipated that KDA-1 probe will find suitable applications in functional proteomics involving human cathepsin B enzyme.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Ferroptosis is a type of non-apoptotic regulated cell death that involves excessive iron accumulation and subsequent lipid peroxidation. Although the antioxidant mechanisms of ferroptosis have been ...extensively studied recently, little is known about the interactions between the different organelles that control ferroptosis. Here, we show that the translocation of lysosomal cysteine protease cathepsin B (CTSB) into the nucleus is an important molecular event that mediates organelle-specific initiation of ferroptosis in human pancreatic cancer cells. Iron-dependent lysosomal membrane permeability triggers the release of CTSB from the lysosome to nucleus during ferroptosis. Mechanistically, nuclear CTSB accumulation causes DNA damage and subsequent activation of the stimulator of interferon response CGAMP interactor 1 (STING1/STING)-dependent DNA sensor pathway, which ultimately leads to autophagy-dependent ferroptosis. Consequently, the genetic inhibition of CTSB-dependent STING1 activation by RNAi prevents ferroptosis in cell culture and animal models. These new findings not only enhance our understanding of the mechanism by which organelles specifically trigger ferroptosis, but also may provide a potential way to enhance the anticancer activity of ferroptosis therapy.
•Increased CTSB expression, activity, and translocation during ferroptosis•CTSB triggers DNA damage and STING1 activation during ferroptosis•CTSB mediates autophagy-dependent ferroptosis•CTSB regulates ferroptosis therapy in vivo
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
10.
Cathepsin B: Multiple roles in cancer Aggarwal, Neha; Sloane, Bonnie F.
Proteomics. Clinical applications,
June 2014, Volume:
8, Issue:
5-6
Journal Article
Peer reviewed
Open access
Proteases, including intracellular proteases, play roles at many different stages of malignant progression. Our focus here is cathepsin B, a lysosomal cysteine cathepsin. High levels of cathepsin B ...are found in a wide variety of human cancers, levels that often induce secretion and association of cathepsin B with the tumor cell membrane. In experimental models, such as transgenic models of murine pancreatic and mammary carcinomas, causal roles for cathepsin B have been demonstrated in initiation, growth/tumor cell proliferation, angiogenesis, invasion, and metastasis. Tumor growth in transgenic models is promoted by cathepsin B in tumor‐associated cells, for example, tumor‐associated macrophages, as well as in tumor cells. In transgenic models, the absence of cathepsin B has been associated with enhanced apoptosis, yet cathepsin B also has been shown to contribute to apoptosis. Cathepsin B is part of a proteolytic pathway identified in xenograft models of human glioma; targeting only cathepsin B in these tumors is less effective than targeting cathepsin B in combination with other proteases or protease receptors. Understanding the mechanisms responsible for increased expression of cathepsin B in tumors and association of cathepsin B with tumor cell membranes is needed to determine whether targeting cathepsin B could be of therapeutic benefit.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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