1.Glucosamine induces cell death via proteasome inhibition in human ALVA41 prostate cancer cell.
Bao Qin LIU ; Xin MENG ; Chao LI ; Yan Yan GAO ; Ning LI ; Xiao Fang NIU ; Yifu GUAN ; Hua Qin WANG
Experimental & Molecular Medicine 2011;43(9):487-493
Glucosamine, a naturally occurring amino monosaccharide, has been reported to play a role in the regulation of apoptosis more than half century. However the effect of glucosamine on tumor cells and the involved molecular mechanisms have not been thoroughly investigated. Glucosamine enters the hexosamine biosynthetic pathway (HBP) downstream of the rate-limiting step catalyzed by the GFAT (glutamine:fluctose-6-phosphate amidotransferase), providing UDP-GlcNAc substrates for O-linked beta-N-acetylglucosamine (O-GlcNAc) protein modification. Considering that O-GlcNAc modification of proteasome subunits inhibits its activity, we examined whether glucosamine induces growth inhibition via affecting proteasomal activity. In the present study, we found glucosamine inhibited proteasomal activity and the proliferation of ALVA41 prostate cancer cells. The inhibition of proteasomal activity results in the accumulation of ubiquitinated proteins, followed by induction of apoptosis. In addition, we demonstrated that glucosamine downregulated proteasome activator PA28gamma and overexpression of PA28gamma rescued the proteasomal activity and growth inhibition mediated by glucosamine. We further demonstrated that inhibition of O-GlcNAc abrogated PA28gamma suppression induced by glucosamine. These findings suggest that glucosamine may inhibit growth of ALVA41 cancer cells through downregulation of PA28gamma and inhibition of proteasomal activity via O-GlcNAc modification.
Acetylglucosamine/chemistry/metabolism
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Alloxan/pharmacology
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Apoptosis/*drug effects
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Autoantigens/genetics/*metabolism
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Cell Line, Tumor
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Cell Proliferation/*drug effects
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Gene Expression Regulation, Neoplastic
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Glucosamine/*pharmacology
;
Humans
;
Male
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Phosphorylation
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Prostatic Neoplasms/*enzymology
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Proteasome Endopeptidase Complex/*antagonists & inhibitors/genetics/metabolism
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RNA, Small Interfering/genetics
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Ubiquitinated Proteins/metabolism
2.Tunicamycin enhances TRAIL-induced apoptosis by inhibition of cyclin D1 and the subsequent downregulation of survivin.
Hai Yan ZHANG ; Zhen Xian DU ; Bao Qin LIU ; Yan Yan GAO ; Xin MENG ; Yifu GUAN ; Wei Wei DENG ; Hua Qin WANG
Experimental & Molecular Medicine 2009;41(5):362-369
TNF-related apoptosis-inducing ligand (TRAIL) has been proposed as a promising cancer therapy that preferentially induces apoptosis in cancer cells, but not most normal tissues. However, many cancers are resistant to TRAIL by mechanisms that are poorly understood. In this study, we showed that tunicamycin, a naturally occurring antibiotic, was a potent enhancer of TRAIL-induced apoptosis through downregulation of survivin. The tunicamycin-mediated sensitization to TRAIL was efficiently reduced by forced expression of survivin, suggesting that the sensitization was mediated at least in part through inhibition of survivin expression. Tunicamycin also repressed expression of cyclin D1, a cell cycle regulator commonly overexpressed in thyroid carcinoma. Furthermore, silencing cyclin D1 by RNA interference reduced survivin expression and sensitized thyroid cancer cells to TRAIL; in contrast, forced expression of cyclin D1 attenuated tunicamycin-potentiated TRAIL-induced apoptosis via over-riding downregulation of survivin. Collectively, our results demonstrated that tunicamycin promoted TRAIL-induced apoptosis, at least in part, by inhibiting the expression of cyclin D1 and subsequent survivin. Of note, tunicamycin did not sensitize the differentiated thyroid epithelial cells to TRAIL-induced apoptosis. Thus, combined treatment with tunicamycin and TRAIL may offer an attractive strategy for safely treating resistant thyroid cancers.
Anti-Bacterial Agents/*pharmacology
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*Apoptosis
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Cell Line, Tumor
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Cyclin D1/*antagonists & inhibitors/metabolism
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*Down-Regulation
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Humans
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Microtubule-Associated Proteins/*genetics/metabolism
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TNF-Related Apoptosis-Inducing Ligand/*metabolism
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Tunicamycin/*pharmacology
3.Tunicamycin enhances TRAIL-induced apoptosis by inhibition of cyclin D1 and the subsequent downregulation of survivin.
Hai Yan ZHANG ; Zhen Xian DU ; Bao Qin LIU ; Yan Yan GAO ; Xin MENG ; Yifu GUAN ; Wei Wei DENG ; Hua Qin WANG
Experimental & Molecular Medicine 2009;41(5):362-369
TNF-related apoptosis-inducing ligand (TRAIL) has been proposed as a promising cancer therapy that preferentially induces apoptosis in cancer cells, but not most normal tissues. However, many cancers are resistant to TRAIL by mechanisms that are poorly understood. In this study, we showed that tunicamycin, a naturally occurring antibiotic, was a potent enhancer of TRAIL-induced apoptosis through downregulation of survivin. The tunicamycin-mediated sensitization to TRAIL was efficiently reduced by forced expression of survivin, suggesting that the sensitization was mediated at least in part through inhibition of survivin expression. Tunicamycin also repressed expression of cyclin D1, a cell cycle regulator commonly overexpressed in thyroid carcinoma. Furthermore, silencing cyclin D1 by RNA interference reduced survivin expression and sensitized thyroid cancer cells to TRAIL; in contrast, forced expression of cyclin D1 attenuated tunicamycin-potentiated TRAIL-induced apoptosis via over-riding downregulation of survivin. Collectively, our results demonstrated that tunicamycin promoted TRAIL-induced apoptosis, at least in part, by inhibiting the expression of cyclin D1 and subsequent survivin. Of note, tunicamycin did not sensitize the differentiated thyroid epithelial cells to TRAIL-induced apoptosis. Thus, combined treatment with tunicamycin and TRAIL may offer an attractive strategy for safely treating resistant thyroid cancers.
Anti-Bacterial Agents/*pharmacology
;
*Apoptosis
;
Cell Line, Tumor
;
Cyclin D1/*antagonists & inhibitors/metabolism
;
*Down-Regulation
;
Humans
;
Microtubule-Associated Proteins/*genetics/metabolism
;
TNF-Related Apoptosis-Inducing Ligand/*metabolism
;
Tunicamycin/*pharmacology