Exp Mol Med.  2011 Sep;43(9):487-493. 10.3858/emm.2011.43.9.055.

Glucosamine induces cell death via proteasome inhibition in human ALVA41 prostate cancer cell

• Liu BQ
• Meng X
• Li C
• Gao YY
• Li N
• Niu XF
• Guan Y
• Wang HQ

• KMID: 1022124
• DOI: http://doi.org/10.3858/emm.2011.43.9.055

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 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.

Keyword

apoptosis; glucosamine; glycosylation; Ki antigen; prostatic neoplasms; proteasome

MeSH Terms

Acetylglucosamine/chemistry/metabolism
Alloxan/pharmacology
Apoptosis/*drug effects
Autoantigens/genetics/*metabolism
Cell Line, Tumor
Cell Proliferation/*drug effects
Gene Expression Regulation, Neoplastic
Glucosamine/*pharmacology
Humans
Male
Phosphorylation
Prostatic Neoplasms/*enzymology
Proteasome Endopeptidase Complex/*antagonists & inhibitors/genetics/metabolism
RNA, Small Interfering/genetics
Ubiquitinated Proteins/metabolism