Department of Biochemistry and Molecular Biology, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110001, China.
Exp Mol Med. 2011 Sep 30;43(9):487-93. doi: 10.3858/emm.2011.43.9.055.
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.
氨基葡萄糖是一种天然存在的单糖，据报道其在调节细胞凋亡方面发挥作用已有半个多世纪。然而，氨基葡萄糖对肿瘤细胞的影响及其涉及的分子机制尚未得到充分研究。氨基葡萄糖进入己糖胺生物合成途径（HBP），该途径位于 GFAT（谷氨酰胺：果糖-6-磷酸酰胺转移酶）催化的限速步骤的下游，为 O-连接β-N-乙酰氨基葡萄糖（O-GlcNAc）蛋白修饰提供 UDPGlcNAc 底物。鉴于蛋白酶体亚基的 O-GlcNAc 修饰抑制其活性，我们研究了氨基葡萄糖是否通过影响蛋白酶体活性来抑制细胞生长。在本研究中，我们发现氨基葡萄糖抑制了前列腺癌细胞 ALVA41 的蛋白酶体活性和增殖。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，我们证明氨基葡萄糖下调了蛋白酶体激活剂 PA28γ，而过表达 PA28γ 可挽救氨基葡萄糖介导的蛋白酶体活性和生长抑制。我们进一步证明，O-GlcNAc 的抑制可消除氨基葡萄糖诱导的 PA28γ 下调。这些发现表明，氨基葡萄糖可能通过下调 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。
