title: Glucosamine induces cell death via proteasome inhibition in human ALVA41 prostate cancer cell.
abstract: 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 UDPGlcNAc substrates for O-linked β-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 PA28γ and overexpression of PA28γ rescued the proteasomal activity and growth inhibition mediated by glucosamine. We further demonstrated that inhibition of O-GlcNAc abrogated PA28γ suppression induced by glucosamine. These findings suggest that glucosamine may inhibit growth of ALVA41 cancer cells through downregulation of PA28γ and inhibition of proteasomal activity via O-GlcNAc modification.
authors.affiliation: Department of Biochemistry and Molecular Biology, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110001, China.
authors.forename: Bao-Qin
authors.initials: BQ
authors.lastname: Liu
authors.forename: Xin
authors.initials: X
authors.lastname: Meng
authors.forename: Chao
authors.initials: C
authors.lastname: Li
authors.forename: Yan-Yan
authors.initials: YY
authors.lastname: Gao
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Niu
authors.forename: Yifu
authors.initials: Y
authors.lastname: Guan
authors.forename: Hua-Qin
authors.initials: HQ
authors.lastname: Wang
mesh_terms: D000117:Acetylglucosamine / Q000737:chemistry / Q000378:metabolism; D000496:Alloxan / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic; D005944:Glucosamine / Q000494:pharmacology*; D006801:Humans; D008297:Male; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000201:enzymology*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D061988:Proteasome Inhibitors; D034741:RNA, Small Interfering / Q000235:genetics; D057149:Ubiquitinated Proteins / Q000378:metabolism
chemical_list: D001324:Autoantigens; C099558:Ki antigen; D061988:Proteasome Inhibitors; D034741:RNA, Small Interfering; D057149:Ubiquitinated Proteins; D000496:Alloxan; D046988:Proteasome Endopeptidase Complex; D005944:Glucosamine; D000117:Acetylglucosamine