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PGK1 facilities cisplatin chemoresistance by triggering HSP90/ERK pathway mediated DNA repair and methylation in endometrial endometrioid adenocarcinoma
Molecular Medicine ( IF 6.0 ) Pub Date : 2019-03-29 , DOI: 10.1186/s10020-019-0079-0
Jing-Wei Zhou , Juan-Juan Tang , Wei Sun , Hui Wang

BackgroundEndometrial carcinoma represents one of the most common cancer types of the female reproductive tract. If diagnosed at an early stage, the 5-year survival rate is promising. However, recurrence and chemoresistance remain problematic for at least 15% of the patients. In the present study, we aim to reveal the mechanism by which PGK1 regulates chemoresistance in endometrial carcinoma.MethodsqPCR was performed to detect expression of PGK1 in clinical tissue samples of endometrial carcinoma. Specific shRNAs were employed to knockdown PGK1 expression in endometrial cancer cell lines. MTT assay was used to evaluate cell viability and cisplatin sensitivity of endometrial carcinoma cell lines. Western blot was performed to assess the effects of PGK1 knockdown on the expression levels of HSP90, DNA repair-associated proteins (c-JUN, FOSL1, and POLD1), and DNA methylation-related enzymes (DNMT1, DNMT3A and DNMT3B). Immunoprecipitation was performed to verify direct binding between PGK1 and HSP90.ResultsWe first showed that PGK1 expression is elevated in tumor tissues of endometrial cancer, and high PGK1 levels are associated with clinical stages and metastasis. Knockdown of PGK1 inhibits proliferation of endometrial cancer cells, and enhances the inhibitory effect of cisplatin on cell viability. In addition, knockdown of PGK1 down-regulates the expression of DNA repair-related proteins, methylation-related enzymes, and total cellular methylation level. PGK1 was next shown to interact directly with HSP90 and exhibit pro-tumor effects by modulating the ATPase activity of HSP90.ConclusionsWe propose that PGK1 mediates DNA repair and methylation through the HSP90/ERK pathway, and eventually enhances the chemoresistance to cisplatin. The results provide new insights on functions of PGK1 and HSP90, which might make them as promising targets for endometrial cancer chemotherapy.

中文翻译:

PGK1通过触发子宫内膜样腺癌中HSP90/ERK通路介导的DNA修复和甲基化来促进顺铂化疗耐药

背景子宫内膜癌是女性生殖道最常见的癌症类型之一。如果早期诊断,5年生存率是有希望的。然而,至少 15% 的患者的复发和化疗耐药性仍然存在问题。本研究旨在揭示PGK1调控子宫内膜癌化疗耐药的机制。方法qPCR检测子宫内膜癌临床组织样本中PGK1的表达。使用特定的 shRNA 来抑制子宫内膜癌细胞系中 PGK1 的表达。MTT法用于评估子宫内膜癌细胞系的细胞活力和顺铂敏感性。进行蛋白质印迹以评估 PGK1 敲低对 HSP90、DNA 修复相关蛋白(c-JUN、FOSL1、和 POLD1),以及 DNA 甲基化相关酶(DNMT1、DNMT3A 和 DNMT3B)。进行免疫沉淀以验证PGK1与HSP90之间的直接结合。结果我们首先表明PGK1在子宫内膜癌的肿瘤组织中表达升高,并且高PGK1水平与临床分期和转移相关。敲低 PGK1 可抑制子宫内膜癌细胞的增殖,并增强顺铂对细胞活力的抑制作用。此外,敲低 PGK1 会下调 DNA 修复相关蛋白、甲基化相关酶和细胞总甲基化水平的表达。接下来显示 PGK1 直接与 HSP90 相互作用并通过调节 HSP90 的 ATPase 活性表现出促肿瘤作用。结论我们认为 PGK1 通过 HSP90/ERK 途径介导 DNA 修复和甲基化,并最终增强对顺铂的耐药性。该结果为 PGK1 和 HSP90 的功能提供了新的见解,这可能使它们成为子宫内膜癌化疗的有希望的靶点。
更新日期:2019-03-29
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