Department of Prosthodontics Dentistry, Hospital of Stomatology, Jilin University, Changchun, China.
NHC Key Laboratory of Radiobiology, Jilin University, Changchun, China.
Sci Rep. 2019 Feb 14;9(1):2111. doi: 10.1038/s41598-019-38585-9.
In this study, we aimed to identify mutations of key genes associated with docetaxel resistance in nine endometrial cancer cell lines. Endometrial cancers are associated with several critical gene mutations, including PIK3A, PTEN, and KRAS. Different gene mutations in endometrial cancer cells have varied responses to anticancer drugs and cancer therapies. The most frequently altered gene in endometrioid endometrial carcinoma tumors is PTEN. PTEN protein has lipid phosphatase and protein phosphatase activity, as well as other functions in the nucleus. Although the tumor-suppressive function of PTEN has mainly been attributed to its lipid phosphatase activity, a role for PTEN protein phosphatase activity in cell cycle regulation has also been suggested. Various tumor type-specific PTEN mutations are well documented. Here, nine endometrioid endometrial cancer cell lines with PIK3A, PTEN, and KRAS gene mutations were treated with docetaxel and radiation. One mutation with a docetaxel drug-resistant effect was a truncated form of PTEN. Among PTEN mutations in endometrial cancer cells, the Y68 frame shift mutation of PTEN constitutes a major mechanism of resistance to docetaxel treatment. The molecular mechanism involves truncation of the 403 amino acid PTEN protein at amino acid 68 by the Y68 frame shift, leading to the loss of PTEN protein phosphatase and lipid phosphatase activities.
在这项研究中，我们旨在确定与 9 种子宫内膜癌细胞系中多西紫杉醇耐药相关的关键基因的突变。子宫内膜癌与几种关键基因突变有关，包括 PIK3A、PTEN 和 KRAS。子宫内膜癌细胞中的不同基因突变对抗癌药物和癌症治疗有不同的反应。在子宫内膜样腺癌肿瘤中最常改变的基因是 PTEN。PTEN 蛋白具有脂质磷酸酶和蛋白磷酸酶活性，以及核内的其他功能。尽管 PTEN 的肿瘤抑制功能主要归因于其脂质磷酸酶活性，但也有人提出 PTEN 蛋白磷酸酶活性在细胞周期调控中的作用。已经充分记录了各种肿瘤类型特异性的 PTEN 突变。在这里，用多西紫杉醇和辐射处理了 9 种具有 PIK3A、PTEN 和 KRAS 基因突变的子宫内膜样癌细胞系。一种具有多西紫杉醇耐药作用的突变是 PTEN 的截断形式。在子宫内膜癌细胞中的 PTEN 突变中，PTEN 的 Y68 移码突变构成了对多西紫杉醇治疗耐药的主要机制。分子机制涉及由 Y68 移码导致的 403 个氨基酸的 PTEN 蛋白在第 68 位截断，导致 PTEN 蛋白磷酸酶和脂质磷酸酶活性丧失。
