Proteasome inhibitor MG132-induced apoptosis via ER stress-mediated apoptotic pathway and its potentiation by protein tyrosine kinase p56lck in human Jurkat T cells

Park, Hae Sun; Jun, Do Youn; Han, Cho Rong; Woo, Hyun Ju; Kim, Young Ho

doi:10.1016/j.bcp.2011.07.085

Cited by 68 publications

(57 citation statements)

References 58 publications

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“…We tested the effect of combining GRP78 siRNA with the ER stress inducers tunicamycin, 2-deoxy-D-glucose or MG132, which have been known to induce GRP78 expression. 27,28) Indeed, combination of transfection with GRP78 siRNA and any of the ER stress inducers more extensively reduced cell viability than combination with scrambled siRNA (Fig. 2).…”

Section: Discussionmentioning

confidence: 93%

Inhibition of Cancer Cell Growth by GRP78 siRNA Lipoplex <i>via</i> Activation of Unfolded Protein Response

Matsumura

Sakai

Kawakami

et al. 2014

Biological & Pharmaceutical Bulletin

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Proteasome inhibitors are a novel class of molecular-targeted anti-cancer drugs that suppress the degradation of malfolded proteins, trigger endoplasmic reticulum (ER) stress, and activate apoptosis signals. Glucose-regulated protein 78 (GRP78), a major ER chaperone, is one of the most important molecules for transduction of unfolded protein response (UPR) signals. In accordance with past findings that expression of GRP78 is elevated in cancer cells and helps to resist stress-induced apoptosis, GRP78 knockdown could be effective in anticancer therapy. We tested this hypothesis and found that transfection of small interfering RNA (siRNA) targeting GRP78 inhibited the growth of RENCA renal carcinoma cells, in association with elevated gene expression of UPR downstream signaling molecules (CHOP, EDEM1, and ERdj4 mRNA). In addition, the combinatorial effect of GRP78 siRNA with ER stress inducers (tunicamycin, MG132, and 2-deoxyglucose) on survival was measured. Combination of GRP78 siRNA and the ER stress inducers more extensively reduced cell viability than combination with scrambled siRNA. Besides RENCA, B16BL6 melanoma cells were also shown to be sensitive to GRP78 siRNA. These results suggest that GRP78 knockdown might be an effective strategy for cancer therapy targeting UPR-induced apoptosis.Key words glucose-regulated protein 78; small interfering RNA; apoptosis; unfolded protein response; endoplasmic reticulum stress; cancer cellThe endoplasmic reticulum (ER) is responsible for protein synthesis, conformational maturation, and quality control of correctly folded proteins. In cancer cells, protein synthesis and by-product disposal are elevated, therefore, disruption of ER functions is believed to be a promising approach for cancer therapy. Proteasome inhibitors, which are a novel class of molecular-targeted anti-cancer drugs, suppress the degradation of malfolded proteins and trigger ER stress, which leads to the activation of the unfolded protein response (UPR) and subsequent apoptotic signals.1,2) Bortezomib was the first approved proteasome inhibitor, and is used for the treatment of relapsed multiple myeloma 3) and mantle cell lymphoma. 4) A second generation of proteasome inhibitors are now under development to improve drug efficacy and compliance. 5)Molecular chaperones are key factors involved in unfolded protein accumulation. Glucose-regulated protein 78 (GRP78) is known as a stress-inducible ER chaperone protein and serves as an ER stress signal regulator.6) Under unstressed conditions, GRP78 associates with ER transmembrane sensor proteins, such as protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme-1 (IRE1) and activating transcription factor 6 (ATF6), 7,8) and these interactions maintain them in an inactive form. However, accumulation of unfolded proteins results in the detachment of GRP78 from the sensor proteins and the subsequent activation of the unfolded protein response (UPR), which results in general translational attenuation, up-regulation of chaperones a...

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Section: Discussionmentioning

confidence: 93%

Inhibition of Cancer Cell Growth by GRP78 siRNA Lipoplex <i>via</i> Activation of Unfolded Protein Response

Matsumura

Sakai

Kawakami

et al. 2014

Biological & Pharmaceutical Bulletin

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“…The extent of necrosis was detected using an Annexin V-FITC apoptosis kit as previously described [28]. The changes in the mitochondrial membrane potential (Dcm) following 2-MeO-E 2 treatment were measured after staining with DiOC 6 [29,30]. Activation of Bak and Bax in Jurkat T cells following 2-MeO-E 2 treatment was measured as previously described [31].…”

Section: Flow Cytometric Analysismentioning

confidence: 99%

Dependency of 2-methoxyestradiol-induced mitochondrial apoptosis on mitotic spindle network impairment and prometaphase arrest in human Jurkat T cells

Lee

Han

et al. 2015

Biochemical Pharmacology

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“…We investigated possible involvement of the proteasomal pathway by treating Jurkat cells for 12 h with STS, Etop, or Dox in the absence or presence of various combinations of Z-VAD and/or MG132, a proteasome inhibitor. MG132 per se is a potent activator of apoptosis in various tumor cell types, including Jurkat cells (40), and proteasome inhibitors are used clinically as cancer chemotherapeutics (41,42). MG132 alone induced cleavage of the Panx1 autoinhibitory domain, which was co-temporal with proteolytic processing PARP1 (Fig.…”

Section: Control (4 H)mentioning

confidence: 99%

Chemotherapeutic Drugs Induce ATP Release via Caspase-gated Pannexin-1 Channels and a Caspase/Pannexin-1-independent Mechanism

Boyd-Tressler

Peñuela

Laird

et al. 2014

Journal of Biological Chemistry

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Background: Pannexin-1 channels mediate ATP efflux and are substrates for apoptotic caspases. Results: Chemotherapeutic drugs induce ATP release via caspase-dependent gating of pannexin-1 channels and a caspase/ pannexin-1-independent mechanism in leukemic lymphocytes. Conclusion: Pannexin-1 channels that release intracellular metabolites are a novel element of cancer chemotherapy. Significance: Pannexin-1 channels link tumor cell apoptosis to purinergic regulation of anti-tumor immunity.

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Proteasome inhibitor MG132-induced apoptosis via ER stress-mediated apoptotic pathway and its potentiation by protein tyrosine kinase p56lck in human Jurkat T cells

Cited by 68 publications

References 58 publications

Inhibition of Cancer Cell Growth by GRP78 siRNA Lipoplex <i>via</i> Activation of Unfolded Protein Response

Inhibition of Cancer Cell Growth by GRP78 siRNA Lipoplex <i>via</i> Activation of Unfolded Protein Response

Dependency of 2-methoxyestradiol-induced mitochondrial apoptosis on mitotic spindle network impairment and prometaphase arrest in human Jurkat T cells

Chemotherapeutic Drugs Induce ATP Release via Caspase-gated Pannexin-1 Channels and a Caspase/Pannexin-1-independent Mechanism

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