{"title":"Plakevulin a 可诱导 HL60 细胞凋亡并抑制 IL-6 诱导的 STAT3 激活。","authors":"","doi":"10.1016/j.bmcl.2024.129886","DOIUrl":null,"url":null,"abstract":"<div><p>(+)-Plakevulin A (<strong>1</strong>), an oxylipin isolated from an Okinawan sponge <em>Plakortis</em> sp. inhibits enzymatic inhibition of DNA polymerases (pols) α and δ and exhibits cytotoxicity against murine leukemia (L1210) and human cervix carcinoma (KB) cell lines. However, the half-maximal inhibitory concentration (IC<sub>50</sub>) value for cytotoxicity significantly differed from those observed for the enzymatic inhibition of pols α and β, indicating the presence of target protein(s) other than pols. This study demonstrated cytotoxicity against human promyelocytic leukemia (HL60), human cervix epithelioid carcinoma (HeLa), mouse calvaria-derived pre-osteoblast (MC3T3-E1), and human normal lung fibroblast (MRC-5) cell lines. This compound had selectivity to cancer cells over normal ones. Among these cell lines, HL60 exhibited the highest sensitivity to (+)-plakevulin A. (+)-Plakevulin A induced DNA fragmentation and caspase-3 activation in HL60 cells, indicating its role in apoptosis induction. Additionally, hydroxysteroid 17-β dehydrogenase 4 (HSD17B4) was isolated from the HL60 lysate as one of its binding proteins through pull-down experiments using its biotinylated derivative and neutravidin-coated beads. Moreover, (+)-plakevulin A suppressed the activation of interleukin 6 (IL-6)-induced signal transducer and activator of transcription 3 (STAT3). Because the knockdown or inhibition of STAT3 induces apoptosis and HSD17B4 regulates STAT3 activation, (+)-plakevulin A may induce apoptosis in HL60 cell lines by suppressing STAT3 activation, potentially by binding to HSD17B4. The present findings provide valuable information for the mechanism of its action.</p></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":2.5000,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Plakevulin A induces apoptosis and suppresses IL-6-induced STAT3 activation in HL60 cells\",\"authors\":\"\",\"doi\":\"10.1016/j.bmcl.2024.129886\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>(+)-Plakevulin A (<strong>1</strong>), an oxylipin isolated from an Okinawan sponge <em>Plakortis</em> sp. inhibits enzymatic inhibition of DNA polymerases (pols) α and δ and exhibits cytotoxicity against murine leukemia (L1210) and human cervix carcinoma (KB) cell lines. However, the half-maximal inhibitory concentration (IC<sub>50</sub>) value for cytotoxicity significantly differed from those observed for the enzymatic inhibition of pols α and β, indicating the presence of target protein(s) other than pols. This study demonstrated cytotoxicity against human promyelocytic leukemia (HL60), human cervix epithelioid carcinoma (HeLa), mouse calvaria-derived pre-osteoblast (MC3T3-E1), and human normal lung fibroblast (MRC-5) cell lines. This compound had selectivity to cancer cells over normal ones. Among these cell lines, HL60 exhibited the highest sensitivity to (+)-plakevulin A. (+)-Plakevulin A induced DNA fragmentation and caspase-3 activation in HL60 cells, indicating its role in apoptosis induction. Additionally, hydroxysteroid 17-β dehydrogenase 4 (HSD17B4) was isolated from the HL60 lysate as one of its binding proteins through pull-down experiments using its biotinylated derivative and neutravidin-coated beads. Moreover, (+)-plakevulin A suppressed the activation of interleukin 6 (IL-6)-induced signal transducer and activator of transcription 3 (STAT3). Because the knockdown or inhibition of STAT3 induces apoptosis and HSD17B4 regulates STAT3 activation, (+)-plakevulin A may induce apoptosis in HL60 cell lines by suppressing STAT3 activation, potentially by binding to HSD17B4. The present findings provide valuable information for the mechanism of its action.</p></div>\",\"PeriodicalId\":256,\"journal\":{\"name\":\"Bioorganic & Medicinal Chemistry Letters\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.5000,\"publicationDate\":\"2024-07-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bioorganic & Medicinal Chemistry Letters\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0960894X24002889\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0960894X24002889","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
引用次数: 0
摘要
(+)-Plakevulin A (1)是从冲绳海绵 Plakortis sp.中分离出来的一种氧脂素,它能抑制 DNA 聚合酶(pols)α 和 δ 的酶抑制作用,并对小鼠白血病(L1210)和人类宫颈癌(KB)细胞株具有细胞毒性。然而,细胞毒性的半数最大抑制浓度(IC50)值与对 pols α 和 β 的酶抑制作用的半数最大抑制浓度(IC50)值明显不同,表明存在 pols 以外的靶蛋白。这项研究证明了该化合物对人类早幼粒细胞白血病(HL60)、人类宫颈上皮样癌(HeLa)、小鼠钙源前成骨细胞(MC3T3-E1)和人类正常肺成纤维细胞(MRC-5)细胞系的细胞毒性。与正常细胞相比,该化合物对癌细胞具有选择性。在这些细胞系中,HL60 对 (+)-Plakevulin A 的敏感性最高。(+)-Plakevulin A 能诱导 HL60 细胞的 DNA 断裂和 caspase-3 激活,表明它在诱导细胞凋亡中的作用。此外,通过使用羟基类固醇 17-β 脱氢酶 4(HSD17B4)的生物素化衍生物和中性印迹蛋白包被的珠子进行牵引实验,从 HL60 细胞裂解液中分离出了羟基类固醇 17-β 脱氢酶 4(HSD17B4),作为其结合蛋白之一。此外,(+)-plakevulin A 还能抑制白细胞介素 6(IL-6)诱导的信号转导子和转录激活子 3(STAT3)的活化。由于 STAT3 的敲除或抑制可诱导细胞凋亡,而 HSD17B4 可调节 STAT3 的活化,因此(+)-白桦脂素 A 可通过抑制 STAT3 的活化来诱导 HL60 细胞株的细胞凋亡,这可能是通过与 HSD17B4 结合来实现的。本研究结果为其作用机制提供了有价值的信息。
Plakevulin A induces apoptosis and suppresses IL-6-induced STAT3 activation in HL60 cells
(+)-Plakevulin A (1), an oxylipin isolated from an Okinawan sponge Plakortis sp. inhibits enzymatic inhibition of DNA polymerases (pols) α and δ and exhibits cytotoxicity against murine leukemia (L1210) and human cervix carcinoma (KB) cell lines. However, the half-maximal inhibitory concentration (IC50) value for cytotoxicity significantly differed from those observed for the enzymatic inhibition of pols α and β, indicating the presence of target protein(s) other than pols. This study demonstrated cytotoxicity against human promyelocytic leukemia (HL60), human cervix epithelioid carcinoma (HeLa), mouse calvaria-derived pre-osteoblast (MC3T3-E1), and human normal lung fibroblast (MRC-5) cell lines. This compound had selectivity to cancer cells over normal ones. Among these cell lines, HL60 exhibited the highest sensitivity to (+)-plakevulin A. (+)-Plakevulin A induced DNA fragmentation and caspase-3 activation in HL60 cells, indicating its role in apoptosis induction. Additionally, hydroxysteroid 17-β dehydrogenase 4 (HSD17B4) was isolated from the HL60 lysate as one of its binding proteins through pull-down experiments using its biotinylated derivative and neutravidin-coated beads. Moreover, (+)-plakevulin A suppressed the activation of interleukin 6 (IL-6)-induced signal transducer and activator of transcription 3 (STAT3). Because the knockdown or inhibition of STAT3 induces apoptosis and HSD17B4 regulates STAT3 activation, (+)-plakevulin A may induce apoptosis in HL60 cell lines by suppressing STAT3 activation, potentially by binding to HSD17B4. The present findings provide valuable information for the mechanism of its action.
期刊介绍:
Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.