PI3K抑制剂林普利塞对弥漫大B细胞淋巴瘤的体外抗肿瘤效应  

Anti⁃tumor effect of PI3K inhibitor Linperlisib on diffuse large B⁃cell lymphoma in vitro

作　　者：张凯敏 黄玉洁 段莹 郭宝平[1] 柯晴[1] 廖成成 岑洪[1] ZHANG Kaimin;HUANG Yujie;DUAN Ying;GUO Baoping;KE Qing;LIAO Chengcheng;CEN Hong(Department of Lympho‑Hematology and Pediatric Oncology,Guangxi Medical University Cancer Hospital,Nanning 530021,China)

机构地区：[1]广西医科大学附属肿瘤医院淋巴血液及儿童肿瘤科,南宁530021

出　　处：《中国癌症防治杂志》2024年第1期56-61,共6页CHINESE JOURNAL OF ONCOLOGY PREVENTION AND TREATMENT

基　　金：广西自然科学基金重点项目(2023GXNSFDA026019);广西医疗卫生重点学科(肿瘤内科);国家自然科学基金项目(82260042)。

摘　　要：目的探讨PI3K抑制剂林普利塞(Linperlisib,YY-20394)对弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma,DLBCL)的抗肿瘤效应及其作用机制。方法采用CCK-8法检测不同浓度YY-20394对SU-DHL-4细胞(GCB亚型)和U2932细胞(ABC亚型)增殖能力的影响,并计算出24 h时药物的IC_(25)、IC_(50)、IC_(75)。采用流式细胞术检测IC_(25)、IC_(50)和IC_(75)浓度YY-20394对SU-DHL-4细胞和U2932细胞凋亡的影响。采用高通量RNA测序技术(RNA-Seq)检测药物作用前后各组细胞基因表达的变化,对差异表达基因进行KEGG信号通路分析和GO富集分析,并且对各组细胞基因表达数据进行GSEA富集分析。结果在YY-20394作用下,SU-DHL-4细胞增殖抑制率和细胞凋亡率增加(P<0.05),但U2932细胞增殖及凋亡能力未发生明显改变(P>0.05)。KEGG和GO富集分析结果显示,YY-20394对SU-DHL-4细胞的抗肿瘤作用涉及多条信号通路,其中PI3K-AKT、MAPK、JAK-STAT等信号通路的活性下调,且可能通过影响醇类物质合成等细胞生物学功能发挥作用;而U2932细胞中未富集到具有显著差异的信号通路。GSEA富集分析显示PI3K-AKT信号通路在SU-DHL-4细胞中的活化水平显著低于U2932细胞。结论PI3K抑制剂YY-20394通过影响PI3K-AKT等肿瘤相关信号通路,对GCB亚型的SU-DHL-4细胞产生抗肿瘤效应,而对ABC亚型的U2932细胞不敏感。Objective To investigate the anti‑tumor effect of PI3K inhibitor YY‑20394 on diffuse large B‑cell lymphoma(DLBCL)in vitro and the underlying mechanism.Methods The effects of different concentrations of YY‑20394 on the proliferation of SU‑DHL‑4 cells(GCB subtybe)and U2932 cells(ABC subtype)were detected by CCK‑8,and the IC_(25),IC_(50)and IC_(75)at 24 h were calculated.The effects of different concentrations(IC_(25)、IC_(50)、IC_(75))of YY‑20394 on the apoptosis of SU‑DHL‑4 cells and U2932 cells were detected by flow cytometry.High‑throughput RNA sequencing technology(RNA‑Seq)was used to detect the changes of gene expression in cells before and after drug action,and the differentially expressed genes were analyzed by KEGG enrichment analysis and GO fumction annotation analysis.Gene expression data of each group of cells were analyzed by GSEA enrichment.Results Under the treatment of YY‑20394,the proliferation inhibition rate and apoptosis rate of SU‑DHL‑4 cells increased(P<0.05),whereas the proliferation and apoptosis ability of U2932 cells changed insignificantly(P>0.05).The results of KEGG enrichment analysis and GO function annotation analysis showed that the anti‑tumor effect of YY‑20394 on SU‑DHL‑4 cells involved several signaling pathways,among which the activities of PI3K‑AKT,AMPK and JAK‑STAT signaling pathways were down‑regulated,and might play a role in affecting cell biological functions such as alcohol synthesis,whereas U2932 cells were not enriched with significantly different signaling pathways.GSEA enrichment analysis showed that the activation level of PI3K‑AKT signaling pathway in SU‑DHL‑4 cells was significantly lower than that of U2932 cells.Conclusions The PI3K inhibitor YY‑20394 induces anti‑tumor effects on the SU‑DHL‑4 cells of GCB subtype by affecting related signaling pathways such as PI3K‑AKT,but does not significantly influence the U2932 cells of ABC subtype.

关 键 词：弥漫大B细胞淋巴瘤 PI3K抑制剂 YY-20394 PI3K-AKT信号通路 RNA测序 

分 类 号：R733.1[医药卫生—肿瘤]