Long‐term cyclosporin A exposure suppresses cathepsin‐B and ‐L activity in gingival fibroblasts

Yamaguchi, Mayumi; Naruishi, Koji; Yamada-Naruishi, Hisa; Omori, Kazuhiro; Nishimura, Fusanori; Takashiba, Shogo

doi:10.1111/j.1600-0765.2004.00746.x

Cited by 30 publications

(34 citation statements)

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“…Transfection of cells with siRNA targeting JNK2 markedly decreased the mitochondrial translocation of cleaved Bax and inhibited the nuclear translocation of AIF and Endo G caused by RH1 treatment ( Figure 6E and F). It has been reported that JNK positively regulates both the activity and expression of cathepsin B, a lysosomal protease involved in caspase-independent apoptosis (Foghsgaard et al, 2001;Tang et al, 2006;Werneburg et al, 2007;Bivik and Ollinger, 2008;Yamaguchi et al, …”

Section: Jnk Activity Is Critical For Generation and Mitochondrial Trmentioning

confidence: 99%

The anti‐tumour compound, RH1, causes mitochondria‐mediated apoptosis by activating c‐Jun N‐terminal kinase

Park¹,

Song²,

Oh³

et al. 2011

British J Pharmacology

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BACKGROUND AND PURPOSE2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone (RH1) is a bioreductive agent that is activated by the two-electron reductase NAD(P)H quinone oxidoreductase 1 (NQO1). Although the cytotoxic efficacy of RH1 against tumours has been studied extensively, the molecular mechanisms underlying this anti-cancer activity have not yet been fully elucidated. EXPERIMENTAL APPROACH2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone-induced apoptosis and related signalling pathways in NQO1-negative and NQO1-overexpressing cells were evaluated. The role of p53 in RH1-induced cell death was investigated using parental and p53-deficient RKO human colorectal cancer cells by assaying clonogenic cell survival. Specific inhibitors and siRNAs targeting factors involved in RH1-induced apoptosis were used to clarify the roles played by such factors in RH1-activated apoptotic signalling pathways. KEY RESULTS2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone induced apoptosis and clonogenic death, dependent on NQO1 and p53. Treatment of NQO1-overexpressing cells with RH1 caused rapid disruption of mitochondrial membrane potential, nuclear translocation of apoptosis-inducing factor (AIF) and endonuclease G (Endo G) from mitochondria, and subsequent caspase-independent apoptotic cell death. siRNA targeting AIF and Endo G effectively attenuated RH1-induced apoptotic cell death. Moreover, RH1 induced cleavage of Bax, which targets mitochondria. RH1 significantly activated the c-Jun N-terminal kinase (JNK) pathway, and inhibition of this pathway suppressed RH1-induced mitochondria-mediated apoptosis. RH1-induced generation and mitochondrial translocation of cleaved Bax were blocked by the JNK inhibitor, SP600125. Inhibition of JNK with SP600125 attenuated the mitochondrial translocation of JNK. CONCLUSIONS AND IMPLICATIONS2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone activated JNK, resulting in mitochondria-mediated apoptotic cell death that was NQO1-dependent. AbbreviationsAIF, apoptosis-inducing factor; DiOC6(3), 3

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Section: Jnk Activity Is Critical For Generation and Mitochondrial Trmentioning

confidence: 99%

The anti‐tumour compound, RH1, causes mitochondria‐mediated apoptosis by activating c‐Jun N‐terminal kinase

Park¹,

Song²,

Oh³

et al. 2011

British J Pharmacology

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“…However, little is known about the molecular target(s) of CsA in HGFs causing gingival overgrowth. In a previous study, we have reported that CsA down-regulates the expression of cathepsin B and L mRNAs in HGFs (Yamada et al 2000;Yamaguchi et al 2004). This finding indicates that CsA suppresses the expression of cathepsin B and L at a transcriptional level.…”

Section: Discussionmentioning

confidence: 99%

“…The MTT assay was performed as described previously (Yamaguchi et al 2004). Cells (2×10 4 ) were seeded in each well of a 96-wells multi plate (Corning Costar, Cambridge, Mass.)…”

Section: Cell Culturementioning

confidence: 99%

“…Cathepsin activities were measured as described previously (Yamada et al 2000;Nishimura et al 2002;Yamaguchi et al 2004). Cells were transiently transfected with dn-or wt-CREB plasmid vectors and cultured with or without 1 μM CA-074 for 3 h.…”

Section: Measurement Of Cathepsin Activitymentioning

confidence: 99%

“…In addition, we have demonstrated that longterm exposure to CsA impairs both cathepsin B and L activity in HGFs (Yamaguchi et al 2004). Importantly, we have observed that mice deficient in the cathepsin L gene manifest enlarged gingiva (Nishimura et al 2002).…”

Section: Introductionmentioning

confidence: 95%

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cAMP-response element binding protein (CREB) regulates cyclosporine-A-mediated down-regulation of cathepsin B and L synthesis

et al. 2007

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Cyclosporin A (CsA) is an immunosuppressant with severe side effects including gingival overgrowth. We have previously reported that CsA impairs the activity of the lysosomal enzymes cathepsin B and L in human gingival fibroblasts (HGFs). Here, we have examined the effects of CsA on the DNA-binding activity of the cyclic AMP response element-binding protein (CREB) and cell viability, and the effects of CREB on cathepsin B and L synthesis and activity in HGFs. We have confirmed that CsA down-regulates cathepsin B and L synthesis. Further, CsA has no effect on cell viability and dramatically impairs CREB-DNA binding activity. Importantly, the synthesis of cathepsin B and L is down-regulated, and their activity is also significantly impaired in HGFs transfected with plasmid expressing dominant-negative CREB. These results suggest that CREB is essential for the CsA-mediated down-regulation of cathepsin B and L synthesis in HGFs.

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IL‐6/sIL‐6R enhances cathepsin B and L production via caveolin‐1‐mediated JNK‐AP‐1 pathway in human gingival fibroblasts

Yamaguchi

Naruishi

Arai

et al. 2008

Journal Cellular Physiology

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Interleukin (IL)-6 has an important role in inflammatory diseases. Lysosomal enzymes cathepsins are widely expressed as cysteine proteases regulating inflammatory process. Caveolin-1 (Cav-1) is a scaffolding/regulatory membrane protein that interacts with signaling molecules. In this study, we investigated the role of Cav-1 on (1) the productivity, and (2) the enzymatic activity of cathepsin B and L in human gingival fibroblasts (HGFs) treated with IL-6 in the presence of soluble form of IL-6 receptor (sIL-6R). At first, we established the siRNA-mediated Cav-1 down-regulating in vitro systems by transient transfection of Cav-1 siRNA. The siRNA-mediated Cav-1 down-regulated cells were treated with IL-6/sIL-6R for indicated times. Then, cell lysates were collected, and examined the IL-6-induced signaling pathway, cathepsin B and L production, and measurement of cathepsins activity. To investigate the cathepsin L activity, cathepsin-(B + L) activity was measured after pretreatment with CA-074Me, a specific inhibitor for cathepsin B. We found that IL-6/sIL-6R enhanced significantly both production and activity of cathepsin B and L in HGFs. Interestingly, IL-6-mediated phosphorylation of both p44/42 MAPK and JNK was dramatically suppressed in Cav-1 down-regulated HGFs treated with IL-6/sIL-6R. In addition, both production and activity of cathepsin B and L were also significantly suppressed. Importantly, we demonstrated that JNK inhibition, but not p44/42 MAPK inhibition, significantly diminished IL-6/sIL-6R-induced cathepsin B and L production. Taken together, we concluded that IL-6/sIL-6R enhances cathepsin B and L production via IL-6/sIL-6R-mediated Cav-1-JNK-AP-1 pathway in HGFs. Our findings indicate that Cav-1 might be a therapeutic target for IL-6-mediated tissue degradation in periodontitis.

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Long‐term cyclosporin A exposure suppresses cathepsin‐B and ‐L activity in gingival fibroblasts

Abstract: The decreased ability of protein degradation by not only cathepsin-L but also cathepsin-B is, at least, one of the several factors developing the cyclosporin A-induced gingival overgrowth.

Cited by 30 publications

References 28 publications

The anti‐tumour compound, RH1, causes mitochondria‐mediated apoptosis by activating c‐Jun N‐terminal kinase

The anti‐tumour compound, RH1, causes mitochondria‐mediated apoptosis by activating c‐Jun N‐terminal kinase

cAMP-response element binding protein (CREB) regulates cyclosporine-A-mediated down-regulation of cathepsin B and L synthesis

IL‐6/sIL‐6R enhances cathepsin B and L production via caveolin‐1‐mediated JNK‐AP‐1 pathway in human gingival fibroblasts

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