Inhibition of N‐linked glycosylation by tunicamycin enhances sensitivity to cisplatin in human head‐and‐neck carcinoma cells

Noda, Ichiro; Fujieda, Shigeharu; Seki, Mizue; Tanaka, Nobuyuki; Sunaga, Hiroshi; Ohtsubo, Toshio; Tsuzuki, Hideaki; Fan, Guo-Kang; Saitô, Hitoshi

doi:10.1002/(sici)1097-0215(19990118)80:2<279::aid-ijc18>3.3.co;2-e

Cited by 28 publications

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“…A previous report showed that tunicamycin increases the sensitivity of head and neck squamous cell carcinoma to cisplatin in vitro and in vivo (20). In the search for new strategies to overcome the resistance of hormone-refractory prostate cancer cells, we found that tunicamycin is a potent enhancer of TRAILinduced apoptosis through induction of DR5 expression in human prostate cancer cells, but not in normal human peripheral blood mononuclear cells (PBMCs).…”

Section: Introductionmentioning

confidence: 80%

Tunicamycin Enhances Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptosis in Human Prostate Cancer Cells

et al. 2005

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Death receptor 5 (DR5/TRAIL-R2) is an apoptosis-inducing membrane receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L). In this study, we showed that tunicamycin, a naturally occurring antibiotic, is a potent enhancer of TRAIL-induced apoptosis through upregulation of DR5 expression. Tunicamycin significantly sensitized PC-3, androgen-independent human prostate cancer cells, to TRAIL-induced apoptosis. The tunicamycinmediated enhancement of TRAIL-induced apoptosis was markedly blocked by a recombinant human DR5/Fc chimeric protein. Tunicamycin and TRAIL cooperatively activated caspase-8, -10, -9, and -3 and Bid cleavage and this activation was also blocked in the presence of the DR5/Fc chimera. Tunicamycin up-regulated DR5 expression at the mRNA and protein levels in a dose-dependent manner. Furthermore, the tunicamycin-mediated sensitization to TRAIL was efficiently reduced by DR5 small interfering RNA, suggesting that the sensitization was mediated through induction of DR5 expression. Tunicamycin increased DR5 promoter activity and this enhanced activity was diminished by mutation of a CHOPbinding site. In addition, suppression of CHOP expression by small interfering RNA reduced the tunicamycin-mediated induction of DR5. Of note, tunicamycin-mediated induction of CHOP and DR5 protein expression was not observed in normal human peripheral blood mononuclear cells. Moreover, tunicamycin did not sensitize the cells to TRAIL-induced apoptosis. Thus, combined treatment with tunicamycin and TRAIL may be a promising candidate for prostate cancer therapy. (Cancer Res 2005; 65(14): 6364-70)

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Section: Introductionmentioning

confidence: 80%

Tunicamycin Enhances Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptosis in Human Prostate Cancer Cells

et al. 2005

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“…While this balance between cytoprotective and apoptotic responses during ER stress has not been fully elucidated, severe induction of UPR by overloading the ER capacity is assumed to enhance cellular sensitivity to chemotherapeutic agents or radiation. For example, cellular sensitivity to cisplatin was increased by the overexpression of GRP78, an abundant ER chaperon [32], or by treatment with tunicamycin, a chemical ER stress inducer [33]. Furthermore, cancer cells treated with acriflavin and also with tunicamycin have been reported to be sensitized to ionizing radiation through the activation of the UPR [34,35,36].…”

Section: Discussionmentioning

confidence: 99%

Radiosensitization of tumor cells through endoplasmic reticulum stress induced by PEGylated nanogel containing gold nanoparticles

et al. 2014

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High atomic number molecules, such as gold and platinum, are known to enhance the biological effect of X-irradiation. This study was aimed to determine the radiosensitizing potential of PEGylated nanogel containing gold nanoparticles (GNG) and the cellular mechanism involved. GNG pretreatment increased the levels of reproductive cell death and apoptosis induced by X-irradiation. GNG accumulated in cytoplasm and increased the expression of endoplasmic reticulum (ER) stress-related protein. GNG suppressed the repair capacity of DNA after X-irradiation by down-regulating DNA repair-related proteins. Our results suggest that GNG radiosensitized cells by enhancing apoptosis and impairing DNA repair capacity via ER stress induction.

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“…TM displays significant cytotoxicity against transformed cells (23)(24)(25)(26), and synergistic effects in combination treatments using TM and antineoplastic drugs [e.g., cisplatin, doxorubicin, vincristine, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), or erlotinib] have been reported (27)(28)(29)(30)(31). Nevertheless, the acute toxicity and small therapeutic window of TM have hampered its use for anticancer therapy so far.…”

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confidence: 99%

A haploid genetic screen identifies the major facilitator domain containing 2A (MFSD2A) transporter as a key mediator in the response to tunicamycin

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et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Tunicamycin (TM) inhibits eukaryotic asparagine-linked glycosylation, protein palmitoylation, ganglioside production, proteoglycan synthesis, 3-hydroxy-3-methylglutaryl coenzyme-A reductase activity, and cell wall biosynthesis in bacteria. Treatment of cells with TM elicits endoplasmic reticulum stress and activates the unfolded protein response. Although widely used in laboratory settings for many years, it is unknown how TM enters cells. Here, we identify in an unbiased genetic screen a transporter of the major facilitator superfamily, major facilitator domain containing 2A (MFSD2A), as a critical mediator of TM toxicity. Cells without MFSD2A are TMresistant, whereas MFSD2A-overexpressing cells are hypersensitive. Hypersensitivity is associated with increased cellular TM uptake concomitant with an enhanced endoplasmic reticulum stress response. Furthermore, MFSD2A mutant analysis reveals an important function of the C terminus for correct intracellular localization and protein stability, and it identifies transmembrane helical amino acid residues essential for mediating TM sensitivity. Overall, our data uncover a critical role for MFSD2A by acting as a putative TM transporter at the plasma membrane.

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Inhibition of N‐linked glycosylation by tunicamycin enhances sensitivity to cisplatin in human head‐and‐neck carcinoma cells

Abstract: Cell-surface glycoproteins play essential roles in maintaining the composition of cell structure. Neoplastic transformation in tumor cells is generally accompanied by structural alterations in cellsurface oligosaccharides (Hakomori, 1996). Alterations in N-linked

Cited by 28 publications

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Tunicamycin Enhances Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptosis in Human Prostate Cancer Cells

Tunicamycin Enhances Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptosis in Human Prostate Cancer Cells

Radiosensitization of tumor cells through endoplasmic reticulum stress induced by PEGylated nanogel containing gold nanoparticles

A haploid genetic screen identifies the major facilitator domain containing 2A (MFSD2A) transporter as a key mediator in the response to tunicamycin

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