Tumor Necrosis Factor‐α Induced Apoptosis in U937 Cells Promotes Cathepsin D‐Independent Stefin B Degradation

Bidovec, Katja; Božič, Janja; Dolenc, Iztok; Turk, Boris; Türk, Vito; Stoka, Veronika

doi:10.1002/jcb.26152

Cited by 6 publications

(6 citation statements)

References 37 publications

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“…A series of studies demonstrated that enzymes such as MMP-2, MMP-9, and uPA generated by tumor cells participated in the proteolytic degradation of the EMC, disrupted the paratumoral anatomy, advanced tumor cells' further penetration, and led to PNI of SACC, eventually ( 9 – 11 ). Cathepsin D (CTSD), a broadly expressed peptidase, belongs to the family of lysosomal aspartic protease, whose most general and basic function is intracellular catabolism in lysosomal compartments ( 12 , 13 ). Besides, it also has been implicated as an important factor in many physiological and pathological processes, such as neovascularization of endothelial progenitor cells, hormone and antigen processing, cell growth, and tissue homeostasis, the metabolic degradation of proteins and peptides, inflammation, and atherosclerosis ( 14 – 16 ).…”

Section: Introductionmentioning

confidence: 99%

Overexpression Cathepsin D Contributes to Perineural Invasion of Salivary Adenoid Cystic Carcinoma

Zhang

Yang

et al. 2018

Front. Oncol.

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Objective: Cathepsin D (CTSD) is a pivotal orchestrator in the occurrence and development of tumors. Recently, CTSD was detected in salivary adenoid cystic carcinoma (SACC). However, its functional role in perineural invasion (PNI) of SACC remained elusive. We conducted the present study to detect the expression of CTSD in SACC, analyze the correlation between CTSD expression and prognosis of SACC patients and elucidate the role of CTSD in occurrence of PNI in SACC to lay the foundation for further studies.Methods: Immunohistochemical analysis was conducted to assess CTSD and Ki67 expression in 158 SACC samples and 20 normal salivary gland samples adjacent to carcinoma. Meanwhile, the correlation between CTSD and PNI of SACC specimens was analyzed using Wilcoxon test. QRT-PCR, immunofluorescence and western blot analysis were used to examine the levels of CTSD mRNA and protein in SACC-LM cell line. SiRNA-mediated CTSD silence was performed. Scratch wound healing assay, transwell invasion assay and DRG co-culture assay of PNI was used to detect the ability of migration, invasion and PNI. FITC-phalloidin was used to detect cytoskeletal organization.Results: Our data demonstrated that the positive expression of CTSD was observed in 74.1% (117/158) of SACC cases, and the expression of CTSD was significantly correlated with the PNI (p < 0.05). The ability of migration, invasion, and PNI could be inhibited significantly by siRNA-mediated CTSD silence (p < 0.01). Furthermore, siRNA-mediated CTSD silence inhibited cytoskeletal organization and pseudo foot formation in SACC-LM cells.Conclusion: Our results suggested that an association between PNI and expression of CTSD existed. CTSD may promote PNI of SACC accompanied by cytoskeletal organization and pseudo foot formation.

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Section: Introductionmentioning

confidence: 99%

Overexpression Cathepsin D Contributes to Perineural Invasion of Salivary Adenoid Cystic Carcinoma

Zhang

Yang

et al. 2018

Front. Oncol.

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“…We recently showed that tumor necrosis factor-αinduced apoptosis in U937 cells proceeds in a timedependent manner, with lysosomal and mitochondrial membrane integrity being affected as early as 1 hour after treatment. 33 Cell-permeable general inhibitors of caspases (z-VAD-fmk), cysteine cathepsins (E64d), or aspartic proteases (PepA-P) did not have inhibitory effects at the cellular level in U937 cells either in tumor necrosis factorα-induced apoptosis 33 or with MD (Figure 4). However, z-VAD-fmk exerted a partial restorative effect on lysosomes, and PepA-P did so on mitochondria, whereas the process was prevented in all three cases by NAC ( Figure 5).…”

Section: Discussionmentioning

confidence: 97%

“…We recently documented that stefin B degradation upon tumor necrosis factor‐α treatment was a gradual process that was more pronounced after a 12‐hour stimulation . Therefore, we tested whether MD treatment might affect stefin B integrity.…”

Section: Discussionmentioning

confidence: 99%

“…We recently documented that stefin B degradation upon tumor necrosis factor-α treatment was a gradual process that was more pronounced after a 12-hour stimulation. 33 Therefore, we tested whether MD treatment might affect stefin B integrity. Within the cytosol, stefin B was degraded by caspases and cathepsin D, a process that was prevented by z-VAD-fmk and partially prevented by PepA-P ( Figure 7).…”

Section: Discussionmentioning

confidence: 99%

“…The bioconjugate, PepA-P, was used for inhibiting cathepsin D due to its enhanced permeability and activity compared with the pentapeptide, pepstatin A. 32 We recently confirmed that in U937 cells, the intracellular activity of cathepsin D was completely prevented upon incubation with PepA-P. 33 It was evident that apoptotic cell death could not be blocked by PepA-P, E64d, or z-VAD-fmk, but was significantly prevented by pretreatment with NAC ( Figure 4).…”

Section: Md-induced Apoptosis In U937mentioning

confidence: 99%

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Menadione‐induced apoptosis in U937 cells involves Bid cleavage and stefin B degradation

Božič

Bidovec

Vizovišek

et al. 2019

J of Cellular Biochemistry

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Earlier studies showed that the oxidant menadione (MD) induces apoptosis in certain cells and also has anticancer effects. Most of these studies emphasized the role of the mitochondria in this process. However, the engagement of other organelles is less known. Particularly, the role of lysosomes and their proteolytic system, which participates in apoptotic cell death, is still unclear. The aim of this study was to investigate the role of lysosomal cathepsins on molecular signaling in MD-induced apoptosis in U937 cells. MD treatment induced translocation of cysteine cathepsins B, C, and S, and aspartic cathepsin D. Once in the cytosol, some cathepsins cleaved the proapoptotic molecule, Bid, in a process that was completely prevented by E64d, a general inhibitor of cysteine cathepsins, and partially prevented by the pancaspase inhibitor, z-VAD-fmk. Upon loss of the mitochondrial membrane potential, apoptosome activation led to caspase-9 processing, activation of caspase-3-like caspases, and poly (ADP-ribose) polymerase cleavage. Notably, the endogenous protein inhibitor, stefin B, was degraded by cathepsin D and caspases. This process was prevented by z-VAD-fmk, and partially by pepstatin A-penetratin.These findings suggest that the cleaved Bid protein acts as an amplifier of apoptotic signaling through mitochondria, thus enhancing the activity of cysteine cathepsins following stefin B degradation. K E Y W O R D S apoptosis, Bid, caspases, cathepsin D, cysteine cathepsins, menadione, stefin B

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Cell Death Pathways: a Novel Therapeutic Approach for Neuroscientists

et al. 2017

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In the first part, the following mechanisms involved in different forms of cell death are considered, with a view to identifying potential therapeutic targets: tumour necrosis factor receptors (TNFRs) and their engagement by tumour necrosis factor-alpha (TNF-α); poly [ADP-ribose] polymerase (PARP)-1 cleavage; the apoptosis signalling kinase (ASK)-c-Jun N-terminal kinase (JNK) axis; lysosomal permeability; activation of programmed necrotic cell death; oxidative stress, caspase-3 inhibition and parthanatos; activation of inflammasomes by reactive oxygen species and the development of pyroptosis; oxidative stress, calcium dyshomeostasis and iron in the development of lysosomal-mediated necrosis and lysosomal membrane permeability; and oxidative stress, lipid peroxidation, iron dyshomeostasis and ferroptosis. In the second part, there is a consideration of the role of lethal and sub-lethal activation of these pathways in the pathogenesis and pathophysiology of neurodegenerative and neuroprogressive disorders, with particular reference to the TNF-α-TNFR signalling axis; dysregulation of ASK-1-JNK signalling; prolonged or chronic PARP-1 activation; the role of pyroptosis and chronic inflammasome activation; and the roles of lysosomal permeabilisation, necroptosis and ferroptosis. Finally, it is suggested that, in addition to targeting oxidative stress and inflammatory processes generally, neuropsychiatric disorders may respond to therapeutic targeting of TNF-α, PARP-1, the Nod-like receptor NLRP3 inflammasome and the necrosomal molecular switch receptor-interacting protein kinase-3, since their widespread activation can drive and/or exacerbate peripheral inflammation and neuroinflammation even in the absence of cell death. To this end, the use is proposed of a combination of the tetracycline derivative minocycline and N-acetylcysteine as adjunctive treatment for a range of neuropsychiatric disorders.

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Tumor Necrosis Factor‐α Induced Apoptosis in U937 Cells Promotes Cathepsin D‐Independent Stefin B Degradation

Cited by 6 publications

References 37 publications

Overexpression Cathepsin D Contributes to Perineural Invasion of Salivary Adenoid Cystic Carcinoma

Overexpression Cathepsin D Contributes to Perineural Invasion of Salivary Adenoid Cystic Carcinoma

Menadione‐induced apoptosis in U937 cells involves Bid cleavage and stefin B degradation

Cell Death Pathways: a Novel Therapeutic Approach for Neuroscientists

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