Glucosamine induces cell death via proteasome inhibition in human ALVA41 prostate cancer cell
Glucosamine induces cell death via proteasome inhibition in human ALVA41 prostate cancer cell
复制标题
葡萄糖胺通过蛋白酶体抑制诱导人 ALVA41 前列腺癌细胞死亡
DOI：
10.3858/emm.2011.43.9.055
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发表时间：
2011-09-30
影响因子：
12.8
通讯作者：
Wang, Hua-Qin
中科院分区：
文献类型：
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作者：
Liu, Bao-Qin;Meng, Xin;Wang, Hua-Qin
氨基葡萄糖是一种天然存在的氨基单糖，半个多世纪以来据报道在细胞凋亡的调节中发挥作用。然而，氨基葡萄糖对肿瘤细胞的影响及其分子机制尚未得到彻底研究。葡萄糖胺进入己糖胺生物合成途径 (HBP)，由 GFAT（谷氨酰胺：氟糖-6-磷酸酰胺转移酶）催化的限速步骤下游，为 O-连接 β-N-乙酰葡萄糖胺 (O-GlcNAc) 蛋白质修饰提供 UDP-GlcNAc 底物。考虑到蛋白酶体亚基的O-GlcNAc修饰会抑制其活性，我们研究了葡萄糖胺是否通过影响蛋白酶体活性来诱导生长抑制。在本研究中，我们发现葡萄糖胺抑制蛋白酶体活性和 ALVA41 前列腺癌细胞的增殖。蛋白酶体活性的抑制导致泛素化蛋白的积累，随后诱导细胞凋亡。此外，我们证明葡萄糖胺下调蛋白酶体激活剂PA28γ，而PA28γ的过度表达可以挽救葡萄糖胺介导的蛋白酶体活性和生长抑制。我们进一步证明，O-GlcNAc 的抑制消除了葡萄糖胺诱导的 PA28γ 抑制。这些发现表明，葡萄糖胺可能通过下调 PA28γ 并通过 O-GlcNAc 修饰抑制蛋白酶体活性来抑制 ALVA41 癌细胞的生长。
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 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.