| 王 成,罗鸣宇,宫淼淼,张铭浩,沈 瑛.磷酸甘油酸变位酶 1 变构抑制剂增强结肠癌细胞对奥沙利铂的敏感性[J].现代生物医学进展英文版,2024,(16):3001-3005. |
| 磷酸甘油酸变位酶 1 变构抑制剂增强结肠癌细胞对奥沙利铂的敏感性 |
| Phosphoglycerate Mutase 1 Allosteric Inhibitor Enhances the Sensitivity of Colon Cancer Cells to Oxalipatin |
| Received:August 21, 2023 Revised:September 17, 2023 |
| DOI：10.13241/j.cnki.pmb.2024.16.001 |
| 中文关键词: PGAM1变构抑制剂 奥沙利铂 结肠癌 CMS |
| 英文关键词: PGAM1 allosteric inhibitor Oxaliplatin Colon cancer CMS |
| 基金项目:上海市高水平地方高校建设项目--药学学科（PT21010） |
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| 中文摘要: |
| 摘要 目的：探究磷酸甘油酸变位酶 1（phosphoglycerate mutase 1, PGAM1）变构抑制剂能否提高结肠癌细胞对奥沙利铂（oxaliplatin, OXA）的敏感性。方法：癌症药物敏感性基因组学（genomics of drug sensitivity in cancer, GDSC）和癌细胞系百科全书数据库（cancer cell line encyclopedia, CCLE）分析四种共识分子亚型 (consensus molecular subgroups, CMS) 结肠癌细胞对OXA敏感性和PGAM1的表达水平；采用CCK8法和 Annexin V/PI双染法，探究PGAM1变构抑制剂HKB99对人源结肠癌细胞增殖和凋亡的作用；采用CCK8法分析HKB99 联合OXA对结肠癌增殖的作用，并进行协同系数分析。结果：首先，GDSC和CCLE数据库分析结果显示，相对于CMS2和CMS3亚型，CMS1和CMS4亚型结肠癌细胞对OXA敏感的细胞比例降低，PGAM1表达升高，具有显著性差异 (P<0.05)。进一步研究表明，HKB99显著抑制不同CMS类型的人源结肠癌SW480、SCUN2B 和DLD-1细胞的增殖，其 IC50均为 1 μM 左右；Annexin V/PI 双染法结果显示，与对照组相比，HKB99处理组DLD-1细胞的凋亡水平显著上升（P<0.01）。最后，CCK8 法检测显示，与OXA单加药组相比，1.5 μM的HKB99显著提高结肠癌DLD-1细胞对OXA的敏感性（IC50: 3.26 vs 0.37 μM）；协同系数分析结果显示，OXA 在浓度1.56 μM和25 μM之间与HKB99的协同系数小于1。结论：本研究发现相对于CMS2和CMS3，CMS1和CMS4结肠癌细胞对OXA敏感性较低且PGAM1表达水平升高，PGAM1 变构抑制剂HKB99增强结肠癌细胞对OXA的敏感性，提示HKB99有望提高结肠癌OXA化疗的敏感性，为患者个体化化疗提供新的治疗策略。 |
| 英文摘要: |
| ABSTRACT Objective: To verify whether phosphoglycerate mutase 1 (PGAM1) allosteric inhibitor could enhance the sensitivity of colon cancer cells to oxaliplatin (OXA). Methods: OXA sensitivity and PGAM1 expression levels of four consensus molecular subgroups (CMS) of colon cancer cells were analyzed according to genomics of drug sensitivity in cancer（GDSC）and cancer cell line encyclopedia (CCLE) databases. CCK8 assay and Annexin V/PI staining were used to investigate the effect of PGAM1 allosteric inhibitor HKB99 on the proliferation and apoptosis of human colon cancer cell lines. CCK8 assay were performed to investigate the effect of HKB99 combined with OXA on the proliferation of colon cancer DLD-1 cells and cooperativity index was analyzed according to the result. Results: Firstly, GDSC and CCLE databases results showed that CMS1 and CMS4 colon cancer cells were less sensitive to OXA than CMS2 and CMS3 cells in terms of the sensitive cells proportion. Compared with, the expression of PGAM1 was higher in CMS1 and CMS4 cells than in CMS1 and CMS3 cells(P<0.05). HKB99 significantly inhibits the proliferation of SW480, SCUN2B and DLD-1 cells, with an IC50 of approximately 1 μM. Annexin V/PI staining results showed that apoptosis of DLD-1 cells was significantly increased compared with Control group after HKB99 treatment(P<0.01). Results of CCK8 assay result showed that 1.5 μM HKB99 significantly enhanced the inhibitory effect of OXA on colon cancer DLD-1 cells compared with control group (IC50: 0.37 vs 3.26 μM）. The cooperativity index analysis result showed that the synergistic coefficient of OXA with HKB99 was less than 1 at the concentration between 1.56 μM and 25 μM. Conclusion: In this study, we found that CMS1 and CMS4 colon cancer cells are less sensitive to OXA and higher level of PGAM1 compared with CMS2 and CMS3 cells. An allosteric inhibitor of PGAM1, HKB99, enhances the sensitivity of colon cancer cells to OXA, which suggests that HKB99 may enhance the sensitivity of OXA chemotherapy and provide a potential treatment strategy for patients with individualized chemotherapy in colon cancer. |
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