Triptolide-induced Cell Death in Pancreatic Cancer Is Mediated by O-GlcNAc Modification of Transcription Factor Sp1
Triptolide-induced Cell Death in Pancreatic Cancer Is Mediated by O-GlcNAc Modification of Transcription Factor Sp1
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DOI：
10.1074/jbc.m113.500983
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发表时间：
2013-11-22
影响因子：
4.8
通讯作者：
Saluja, Ashok K.
中科院分区：
文献类型：
--
作者：
Banerjee, Sulagna;Sangwan, Veena;Saluja, Ashok K.
胰腺癌是美国第四大常见的癌症相关死亡原因，诊断后5年生存率为5%。HSP 70是一种具有逃避细胞死亡的非凡能力的生存蛋白。一种天然衍生化合物雷公藤内酯醇及其水溶性前药Minnelide下调胰腺癌细胞中该蛋白的表达，从而导致细胞死亡。然而，雷公藤内酯醇的作用机制尚未阐明。我们的研究表明，雷公藤甲素诱导的HSP 70表达下调与转录因子Sp1糖基化的减少有关。我们进一步表明，雷公藤内酯醇抑制Sp1的糖基化，抑制己糖胺生物合成途径，特别是酶O-GlcNAc转移酶。抑制O-GlcNAc转移酶可阻止Sp1的核定位并影响其DNA结合活性。这反过来又下调了促生存途径，如NF-B，导致HSF 1和HSP 70的抑制，最终导致细胞死亡。在这项研究中，我们评估了雷公藤内酯醇影响Sp1糖基化的机制，这反过来又影响了控制胰腺癌细胞存活的下游途径。
Pancreatic cancer, the fourth most prevalent cancer-related cause of death in the United States, is a disease with a dismal survival rate of 5% 5 years after diagnosis. One of the survival proteins responsible for its extraordinary ability to evade cell death is HSP70. A naturally derived compound, triptolide, and its water-soluble prodrug, Minnelide, down-regulate the expression of this protein in pancreatic cancer cells, thereby causing cell death. However, the mechanism of action of triptolide has not been elucidated. Our study shows that triptolide-induced down-regulation of HSP70 expression is associated with a decrease in glycosylation of the transcription factor Sp1. We further show that triptolide inhibits glycosylation of Sp1, inhibiting the hexosamine biosynthesis pathway, particularly the enzyme O-GlcNAc transferase. Inhibition of O-GlcNAc transferase prevents nuclear localization of Sp1 and affects its DNA binding activity. This in turn down-regulates prosurvival pathways like NF-B, leading to inhibition of HSF1 and HSP70 and eventually to cell death. In this study, we evaluated the mechanism by which triptolide affects glycosylation of Sp1, which in turn affects downstream pathways controlling survival of pancreatic cancer cells.