Wang Yuan, Jiang Xue-Yan, Yu Xi-Yong
Key Laboratory of Molecular Target and Clinical Pharmacology, School of Pharmaceutical Sciences and the Affiliated Fifth Hospital, Guangzhou Medical University, Guangzhou 511436, China.
Transl Cancer Res. 2020 May;9(5):3354-3366. doi: 10.21037/tcr.2020.03.67.
First-line chemotherapeutic agents lead to remarkable activation treatment in cancers, but the side effects of these drugs also damage healthy cells. In some cases, drug resistance to chemotherapeutic agents is induced in cancer cells. The molecular mechanisms underlying such a side effect have been studied in a range of cancer types, yet little is known about how the adverse effects of chemotherapeutic drugs can be diminished by targeting bromodomain-containing protein 9 (BRD9) in gastric cancers.
We used two gastric cancer cell lines (MGC-803 and AGS) for comparison. We applied molecular and cellular techniques to measure cell survival and mRNA expression, investigated clinical data in the consensus of The Cancer Genome Atlas, and utilized high-throughput sequencing in MGC-803 cells and AGS cells for global gene expression analysis in inhibiting BRD9 conditions.
Our studies showed that cancer cells with BRD9 overexpression, MGC-803 cells, were more sensitive to BRD9 inhibitors (i.e., BI9564 or BI7273) than AGS cells. The mechanism of BRD9 was related to the regulation of calcium voltage-gated channel auxiliary subunit alpha2 delta 4 (CANA2D4), calmodulin-like 6 (CALML6), guanine nucleotide binding protein (G protein), alpha activating activity polypeptide O (GNAO1) and Potassium Inwardly Rectifying Channel Subfamily J, Member 5 (KCNJ5) oncogenes in the oxytocin signaling pathway. BRD9 inhibitors could enhance the sensitivity of gastric cancer MGC-803 cells to adriamycin and cisplatin, so we may reduce the dosage of chemotherapeutic agents in curing gastric cancers with BRD9 over expression by combining BI9564 or BI7273 with adriamycin or cisplatin.
Our study elucidated the feasibility and effectiveness of inhibiting BRD9 to reduce the adverse effects of first-line chemotherapeutic agents in treating gastric cancer with BRD9 overexpression. This study provides a scientific theoretical basis for a chemotherapy regimen in gastric cancer with BRD9 overexpression.
一线化疗药物在癌症治疗中能引发显著的激活作用，但这些药物的副作用也会损害健康细胞。在某些情况下，癌细胞会对化疗药物产生耐药性。虽然已经在多种癌症类型中研究了这种副作用背后的分子机制，但对于如何通过靶向含溴结构域蛋白9（BRD9）来减轻胃癌中化疗药物的不良反应却知之甚少。
我们使用了两种胃癌细胞系（MGC - 803和AGS）进行比较。我们应用分子和细胞技术来测量细胞存活率和mRNA表达，在癌症基因组图谱共识中研究临床数据，并在MGC - 803细胞和AGS细胞中利用高通量测序进行在抑制BRD9条件下的全基因表达分析。
我们的研究表明，BRD9过表达的癌细胞，即MGC - 803细胞，比AGS细胞对BRD9抑制剂（即BI9564或BI7273）更敏感。BRD9的作用机制与催产素信号通路中钙电压门控通道辅助亚基α2δ4（CANA2D4）、钙调蛋白样6（CALML6）、鸟嘌呤核苷酸结合蛋白（G蛋白）、α激活活性多肽O（GNAO1）和内向整流钾通道亚家族J成员5（KCNJ5）癌基因的调控有关。BRD9抑制剂可增强胃癌MGC - 803细胞对阿霉素和顺铂的敏感性，因此通过将BI9564或BI7273与阿霉素或顺铂联合使用，我们可能在治疗BRD9过表达的胃癌时减少化疗药物的剂量。
我们的研究阐明了抑制BRD9以减少一线化疗药物在治疗BRD9过表达胃癌时不良反应的可行性和有效性。本研究为BRD9过表达的胃癌化疗方案提供了科学的理论依据。
