Overexpression and significance of prion protein in gastric cancer and multidrug-resistant gastric carcinoma cell line SGC7901/ADR
Overexpression and significance of prion protein in gastric cancer and multidrug-resistant gastric carcinoma cell line SGC7901/ADR
复制标题
DOI：
10.1002/ijc.20570
复制
发表时间：
2005-01-10
影响因子：
6.4
通讯作者：
Fan, DM
中科院分区：
文献类型：
--
作者：
Du, JP;Pan, YL;Fan, DM
在我们以前的工作中，细胞朊蛋白（PrPc）被确定为阿霉素耐药胃癌细胞系SGC 7901/ADR中的上调基因，与其亲本细胞系SGC 7901相比。本研究旨在探讨PrPc在胃癌中的表达及其与胃癌多药耐药（MDR）的关系。我们证明PrPc在胃癌细胞系和组织中普遍表达。PrPc使SGC 7901对P-糖蛋白（P-gp）相关和P-gp非相关药物产生耐药性，并伴随着PrPc过表达细胞中阿霉素蓄积减少和释放量增加。通过反义或RNAi技术抑制PrPc表达可部分逆转SGC 7901/ADR的多药耐药表型。PrPe显著上调经典MDR相关分子P-gp的表达，但不上调多药耐药相关蛋白和谷胱甘肽S-转移酶pi的表达。P-gp抑制剂维拉帕米可部分逆转PrPc诱导的MDR。PrPc还能抑制阿霉素诱导的细胞凋亡，改变Bcl-2和Bax的表达，这可能是PrPc介导MDR的另一途径。对PrPc生物学功能的深入研究，将有助于了解临床胃癌的发生、发展及PrPc相关MDR的机制，为胃癌的治疗提供可能的策略。
In our previous work, cellular prion protein (PrPc) was identified as an upregulated gene in adriamycin-resistant gastric carcinoma cell line SGC7901/ADR compared to its parental cell line SGC7901. Here we investigate the expression of PrPc in gastric cancer and whether it was involved in multidrug resistance (MDR) of gastric cancer. We demonstrated that PrPc was ubiquitously expressed in gastric cancer cell lines and tissues. PrPc conferred resistance of both P-glycoprotein (P-gp)-related and P-gp-nonrelated drugs on SGC7901, which was accompanied by decreased accumulation and increased releasing amount of adriamycin in PrPc-overexpressing cell line. Inhibition of PrPc expression by antisense or RNAi technology could partially reverse multidrug-resistant phenotype of SGC7901/ADR. PrPe significantly upregulated the expression of the classical MDR-related molecule P-gp but not multidrug resistance associated protein and glutathione S-transferase pi. The PrPc-induced MDR could be partially reversed by P-gp inhibitor verapamil. PrPc could also suppress adriamycin-induced apoptosis and alter the expression of Bcl-2 and Bax, which might be another pathway contributing to PrPc-related MDR. The further study of the biological functions of PrPc may be helpful for understanding the mechanisms of occurrence and development of clinical gastric carcinoma and PrPc-related MDR and developing possible strategies to treat gastric cancer.