Upregulation of Beclin-1 expression and phosphorylation of Bcl-2 and p53 are involved in the JNK-mediated autophagic cell death

Park, Kyung Jin; Lee, Seung Hyun; Lee, Chang Han; Jang, Ji Young; Chung, Junho; Kwon, Myung Hee; Kim, Yong‐Sung

doi:10.1016/j.bbrc.2009.03.095

Cited by 108 publications

(77 citation statements)

References 22 publications

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“…Cell Viability Assays Unless specified otherwise, human cell lines were purchased from the American Type Culture Collection and maintained as described previously (13,30). Wild-type HCT116 and its Bax-deficient (Bax −/− ) and p53-deficient (p53 −/− ) cell lines were obtained from the Cell Center of John's Hopkins University School of Medicine (30,31).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Wild-type HCT116 and its Bax-deficient (Bax −/− ) and p53-deficient (p53 −/− ) cell lines were obtained from the Cell Center of John's Hopkins University School of Medicine (30,31). Jurkat E6-1 clone and Jurkat A3 clone cells were from the American Type Culture Collection and Korean Cell Line Bank, respectively (30). Jurkat A3 clone and its mutant cell lines deficient in receptor-interacting protein 1 (RIP1; RIP1 deficient), caspase-8 (Jurkat I9.2), and FADD (Jurkat I2.1) were kindly provided by Prof. John Blenis (Department of Cell Biology, Harvard Medical School, Boston, MA; refs.…”

Section: Methodsmentioning

confidence: 99%

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A novel agonistic antibody to human death receptor 4 induces apoptotic cell death in various tumor cells without cytotoxicity in hepatocytes

Sung

Park²,

Lee³

et al. 2009

Molecular Cancer Therapeutics

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The proapoptotic tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptors death receptor (DR) 4 and DR5 are attractive targets to develop the receptorspecific agonistic monoclonal antibodies (mAb) as anticancer agents because of their tumor-selective cell death-inducing activity. Here, we report a novel agonistic mAb, AY4, raised against human DR4 in mice. ELISA analysis revealed that AY4 specifically bound to DR4 without competition with TRAIL for the binding. Despite distinct binding regions of AY4 on DR4 from those of TRAIL, AY4 as a single agent induced caspase-dependent apoptotic cell death of several tumor types through the extrinsic and/or intrinsic pathways without substantial cytotoxicity to normal human hepatocytes. Further, the AY4-sensitive cells followed the same cell death characteristics classified as type I and type II cells by the response to TRAIL, suggesting that the cell death profiles in responses to DR4 and/or DR5 stimulation are determined by the downstream signaling of the receptor rather than the kind of receptor. Noticeably, AY4 efficiently induced cell death of Jurkat cells, which have been reported to be resistant to other anti-DR4 agonistic mAbs, most likely due to the unique epitope property of AY4. In vivo administration of AY4 significantly inhibited tumor growth of human non-small cell lung carcinoma preestablished in athymic nude mice. Conclusively, our results provide further insight into the DR4-mediated cell death signaling and potential use of AY4 mAb as an anticancer therapeutic agent, particularly for

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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A novel agonistic antibody to human death receptor 4 induces apoptotic cell death in various tumor cells without cytotoxicity in hepatocytes

Sung

Park²,

Lee³

et al. 2009

Molecular Cancer Therapeutics

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“…Effects of caspase inhibitor were examined by first pretreating cells for 0.5 h with Z-VADfmk, Z-IETD-fmk or Z-LEAD-fmk before subsequent treatment with the other agents. Cell viability was analyzed using a colorimetric MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide)-based cell growth determination kit (Sigma) and data were presented as a percentage relative to untreated control cells using the following formula: cell viability (%) = (absorbance of sample treated cells -blank wells)/(absorbance of untreated wells -blank wells) 9 100 [31,32]. The results are presented as mean ± standard deviation (SD) values from at least three independent experiments.…”

Section: Cell Viability Assaysmentioning

confidence: 99%

“…A standard procedure for Western blotting was performed as described previously [28,32]. The horseradish peroxidase conjugated anti-rabbit or anti-mouse IgG was used to visualize proteins via an enhanced chemiluminescence system (ECL, Thermo Scientific Inc, Rockford, IL).…”

Section: Western Blotting Analysismentioning

confidence: 99%

Histone deacetylase inhibitors synergistically potentiate death receptor 4-mediated apoptotic cell death of human T-cell acute lymphoblastic leukemia cells

et al. 2010

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Cell-death signaling through the pro-apoptotic tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptors, death receptor 4 (DR4) and DR5, has shown tumor-selective apoptotic activity. Here, we examine susceptibility of various leukemia cell lines (HL-60, U937, K562, CCRF-CEM, CEM-CM3, and THP-1) to an anti-DR4 agonistic monoclonal antibody (mAb), AY4, in comparison with TRAIL. While most of the leukemia cell lines were intrinsically resistant to AY4 or TRAIL alone, the two T-cell acute lymphoblastic leukemia (T-ALL) lines, CEM-CM3 and CCRF-CEM cells, underwent synergistic caspase-dependent apoptotic cell death by combination of AY4 or TRAIL with a histone deacetylase inhibitor (HDACI), either suberoylanilide hydroxamic acid (SAHA) or valproic acid (VPA). All of the combined treatments synergistically downregulated several antiapoptotic proteins (c-FLIP, Bcl-2, Bcl-X L , XIAP, and survivin) without significant changing the expression levels of pro-apoptotic proteins (Bax and Bak) or the receptors (DR4 and DR5). Downregulation of c-FLIP to activate caspase-8 was a critical step for the synergistic apoptosis through both extrinsic and intrinsic apoptotic pathways. Our results demonstrate that the HDACIs have synergistic effects on DR4-specific mAb AY4-mediated cell death in the T-ALL cells with comparable competence to those exerted by TRAIL, providing a new strategy for the targeted treatment of human T-ALL cells.

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The role of TRAIL in mediating autophagy in myositis skeletal muscle: A potential nonimmune mechanism of muscle damage

Alger¹,

Raben²,

Pistilli³

et al. 2011

Arthritis & Rheumatism

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Objective Multinucleated cells are relatively resistant to classical apoptosis, and the factors initiating cell-death and damage in myositis are not well defined. We hypothesized that non-immune autophagic cell death may play a role in muscle fiber damage. Recent literature indicates that tumor necrosis factor-alpha-related apoptosis inducing ligand (TRAIL) may induce both NFκB (nuclear factor kappa-light chain enhancer of activated B cells) activation and autophagic cell death in other systems. Here, we have investigated its role in cell death and pathogenesis in vitro and in vivo using myositis (human and mouse) muscle tissues. Methods Gene expression profiling indicated that expression of TRAIL and several autophagy markers was specifically upregulated in myositis muscle tissue; these results were confirmed by immunohistochemistry and immunoblotting. We also analyzed TRAIL-induced cell death (apoptosis and autophagy) and NFκB activation in vitro in cultured cells. Results TRAIL was expressed predominantly in muscle fibers of myositis, but not in biopsies from normal or other dystrophic-diseased muscle. Autophagy markers were upregulated in human and mouse models of myositis. TRAIL expression was restricted to regenerating/atrophic areas of muscle fascicles, blood vessels, and infiltrating lymphocytes. TRAIL induced NFκB activation and IκB degradation in cultured cells that are resistant to TRAIL-induced apoptosis but undergo autophagic cell death. Conclusion Our data demonstrate that TRAIL is expressed in myositis muscle and may mediate both activation of NFκB and autophagic cell death in myositis. Thus, this non-immune pathway may be an attractive target for therapeutic intervention in myositis.

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Upregulation of Beclin-1 expression and phosphorylation of Bcl-2 and p53 are involved in the JNK-mediated autophagic cell death

Cited by 108 publications

References 22 publications

A novel agonistic antibody to human death receptor 4 induces apoptotic cell death in various tumor cells without cytotoxicity in hepatocytes

A novel agonistic antibody to human death receptor 4 induces apoptotic cell death in various tumor cells without cytotoxicity in hepatocytes

Histone deacetylase inhibitors synergistically potentiate death receptor 4-mediated apoptotic cell death of human T-cell acute lymphoblastic leukemia cells

The role of TRAIL in mediating autophagy in myositis skeletal muscle: A potential nonimmune mechanism of muscle damage

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