Ji Zhi-Peng, Qiang Ling, Zhang Jian-Liang
Department of General Surgery, The Second Hospital of Shandong University, Jinan, Shandong 250033, P.R. China.
Department of Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, Shandong 250117, P.R. China.
Exp Ther Med. 2018 Feb;15(2):1831-1838. doi: 10.3892/etm.2017.5642. Epub 2017 Dec 15.
Gastric cancer (GC) is one of the leading types of cancer in terms of mortality cases worldwide. Doxorubicin (Dox), a common chemotherapy drug, is frequently used to treat GC; however, acquired resistance to Dox hinders the chemotherapeutic outcome and causes shorter survival in GC patients. Several Dox-resistant GC cell lines, including SGC7901, SNU-1 and SNU-5 were generated to investigate the mechanism of Dox resistance in GC. Various methods were used to test the response of Dox-resistant GC cells and parental cells, including flow cytometry, Cell Counting kit-8 assay, reverse transcription polymerase chain reaction and western blot analysis. In the present study, various Dox-resistant cells presented reduced apoptosis and cell cycle arrest in response to Dox treatment. Western blot results revealed that cyclin D1 was upregulated in Dox-resistant cells, whereas inhibition or depletion of cyclin D1 re-sensitized the resistant cells to Dox treatment, which indicated that the induction of cyclin D1 expression was a result of the Dox resistance in GC cells. Furthermore, it was observed that a transcription activated form of p73 (TAp73), is the upstream modulator of cyclin D1, manipulating the cyclin D1 transcription with the assistance of activator protein 1 (AP-1). Overall, the present study data provided a rational strategy to overcome the Dox resistance in GC treatment by inhibiting cyclin D1 expression.
胃癌（GC）是全球范围内导致死亡病例最多的主要癌症类型之一。阿霉素（Dox）是一种常用的化疗药物，常用于治疗GC；然而，对Dox产生的获得性耐药性阻碍了化疗效果，并导致GC患者生存期缩短。为了研究GC中Dox耐药的机制，构建了几种对Dox耐药的GC细胞系，包括SGC7901、SNU-1和SNU-5。采用多种方法检测对Dox耐药的GC细胞和亲本细胞的反应，包括流式细胞术、细胞计数试剂盒-8检测、逆转录聚合酶链反应和蛋白质免疫印迹分析。在本研究中，各种对Dox耐药的细胞在接受Dox处理后凋亡减少且细胞周期停滞。蛋白质免疫印迹结果显示，细胞周期蛋白D1在对Dox耐药的细胞中上调，而抑制或去除细胞周期蛋白D1可使耐药细胞对Dox处理重新敏感，这表明细胞周期蛋白D1表达的诱导是GC细胞中Dox耐药的结果。此外，研究发现转录激活形式的p73（TAp73）是细胞周期蛋白D1的上游调节因子，在激活蛋白1（AP-1）的协助下调控细胞周期蛋白D1的转录。总体而言，本研究数据提供了一种通过抑制细胞周期蛋白D1表达来克服GC治疗中Dox耐药的合理策略。
