• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

洛那法尼布与索拉非尼联合用药通过ATG3介导的自噬通量诱导肝癌细胞中细胞周期蛋白D1降解。

The combination of lonafarnib and sorafenib induces cyclin D1 degradation via ATG3-mediated autophagic flux in hepatocellular carcinoma cells.

作者信息

Wang Jialiang, Wei Huan, Huang Yanlin, Chen Dongmei, Zeng Guofen, Lian Yifan, Huang Yuehua

机构信息

Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.

出版信息

Aging (Albany NY). 2019 Aug 13;11(15):5769-5785. doi: 10.18632/aging.102165.

DOI:10.18632/aging.102165
PMID:31409760
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6710066/
Abstract

Combination treatment is a promising strategy to improve prognosis of hepatocellular carcinoma (HCC). Sorafenib is a traditional first-line agent approved for the treatment of advanced HCC, though with limited efficacy. Previously, we reported that lonafarnib, an orally bioavailable non-peptide inhibitor targeting farnesyltransferase, synergizes with sorafenib against the growth of HCC cells. In the present study, we aim to clarify the underlying mechanism of this combination strategy. Initially, using in vitro HCC cell model, we confirmed that synergistic treatment of lonafarnib and sorafenib suppressed cell viability and colony formation, and induced cell death. We then found conversion of LC3-I to LC3-II via combination the treatment and observed formation of autophagosomes by electron microscopy. Knockdown of ATG3 inhibited the autophagic flux induced by the combination treatment. Furthermore, we demonstrated that drug-eliciting autophagy selectively promoted the degradation of cyclin D1 in a lysosome-dependent manner and subsequently inhibited DNA synthesis through downregulating the phosphorylation of Rb protein. In conclusion, our results provide a deeper insight into the mechanism for the combination treatment of lonafarnib and sorafenib in HCC therapy.

摘要

联合治疗是改善肝细胞癌（HCC）预后的一种有前景的策略。索拉非尼是一种被批准用于治疗晚期HCC的传统一线药物，但其疗效有限。此前，我们报道了一种口服生物可利用的靶向法尼基转移酶的非肽抑制剂洛那法尼，它与索拉非尼协同作用可抑制HCC细胞的生长。在本研究中，我们旨在阐明这种联合策略的潜在机制。首先，使用体外HCC细胞模型，我们证实洛那法尼和索拉非尼的联合治疗可抑制细胞活力和集落形成，并诱导细胞死亡。然后我们发现联合治疗可使LC3-I转化为LC3-II，并通过电子显微镜观察到自噬体的形成。敲低ATG3可抑制联合治疗诱导的自噬流。此外，我们证明药物诱导的自噬以溶酶体依赖的方式选择性促进细胞周期蛋白D1的降解，随后通过下调Rb蛋白的磷酸化来抑制DNA合成。总之，我们的结果为洛那法尼和索拉非尼联合治疗HCC的机制提供了更深入的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0f0/6710066/13484df4a599/aging-11-102165-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0f0/6710066/2bcf9b7d6750/aging-11-102165-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0f0/6710066/2c6f4920a002/aging-11-102165-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0f0/6710066/acc070ec4068/aging-11-102165-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0f0/6710066/a7cc2e7335a8/aging-11-102165-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0f0/6710066/fd971b0ef9ea/aging-11-102165-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0f0/6710066/863b8544dcbd/aging-11-102165-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0f0/6710066/60d97a6c2877/aging-11-102165-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0f0/6710066/13484df4a599/aging-11-102165-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0f0/6710066/2bcf9b7d6750/aging-11-102165-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0f0/6710066/2c6f4920a002/aging-11-102165-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0f0/6710066/acc070ec4068/aging-11-102165-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0f0/6710066/a7cc2e7335a8/aging-11-102165-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0f0/6710066/fd971b0ef9ea/aging-11-102165-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0f0/6710066/863b8544dcbd/aging-11-102165-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0f0/6710066/60d97a6c2877/aging-11-102165-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f0f0/6710066/13484df4a599/aging-11-102165-g008.jpg

相似文献

1
The combination of lonafarnib and sorafenib induces cyclin D1 degradation via ATG3-mediated autophagic flux in hepatocellular carcinoma cells.洛那法尼布与索拉非尼联合用药通过ATG3介导的自噬通量诱导肝癌细胞中细胞周期蛋白D1降解。
Aging (Albany NY). 2019 Aug 13;11(15):5769-5785. doi: 10.18632/aging.102165.
2
Inhibition of autophagy potentiates the antitumor effect of the multikinase inhibitor sorafenib in hepatocellular carcinoma.自噬抑制增强多激酶抑制剂索拉非尼对肝癌的抗肿瘤作用。
Int J Cancer. 2012 Aug 1;131(3):548-57. doi: 10.1002/ijc.26374. Epub 2011 Sep 12.
3
2-Methoxyestradiol synergizes with sorafenib to suppress hepatocellular carcinoma by simultaneously dysregulating hypoxia-inducible factor-1 and -2.2-甲氧基雌二醇通过同时失调缺氧诱导因子-1 和 -2 协同索拉非尼抑制肝细胞癌。
Cancer Lett. 2014 Dec 1;355(1):96-105. doi: 10.1016/j.canlet.2014.09.011. Epub 2014 Sep 11.
4
A novel multitarget kinase inhibitor BZG with potent anticancer activity in vitro and vivo enhances efficacy of sorafenib through PI3K pathways in hepatocellular carcinoma cells.一种新型的多靶点激酶抑制剂 BZG，在体外和体内具有强大的抗癌活性，通过 PI3K 通路增强肝癌细胞中索拉非尼的疗效。
Biomed Pharmacother. 2020 May;125:110033. doi: 10.1016/j.biopha.2020.110033. Epub 2020 Feb 25.
5
Co-delivery of sorafenib and metapristone encapsulated by CXCR4-targeted PLGA-PEG nanoparticles overcomes hepatocellular carcinoma resistance to sorafenib.载sorafenib 和米非司酮的 CXCR4 靶向 PLGA-PEG 纳米粒共递送克服了肝细胞癌对 sorafenib 的耐药性。
J Exp Clin Cancer Res. 2019 May 31;38(1):232. doi: 10.1186/s13046-019-1216-x.
6
Inhibition of doxorubicin-induced autophagy in hepatocellular carcinoma Hep3B cells by sorafenib--the role of extracellular signal-regulated kinase counteraction.索拉非尼抑制多柔比星诱导的肝癌 Hep3B 细胞自噬——细胞外信号调节激酶拮抗作用的角色。
FEBS J. 2011 Sep;278(18):3494-507. doi: 10.1111/j.1742-4658.2011.08271.x.
7
LncRNA NEAT1 promotes autophagy via regulating miR-204/ATG3 and enhanced cell resistance to sorafenib in hepatocellular carcinoma.长链非编码 RNA NEAT1 通过调控 miR-204/ATG3 促进自噬并增强肝癌细胞对索拉非尼的耐药性。
J Cell Physiol. 2020 Apr;235(4):3402-3413. doi: 10.1002/jcp.29230. Epub 2019 Sep 23.
8
Synergistic effects of α-Mangostin and sorafenib in hepatocellular carcinoma: New insights into α-mangostin cytotoxicity.α-倒捻子素与索拉非尼在肝细胞癌中的协同作用：对 α-倒捻子素细胞毒性的新认识。
Biochem Biophys Res Commun. 2021 Jun 18;558:14-21. doi: 10.1016/j.bbrc.2021.04.047. Epub 2021 Apr 22.
9
Autophagic flux modulation by Wnt/β-catenin pathway inhibition in hepatocellular carcinoma.Wnt/β-catenin 通路抑制调控肝癌自噬流。
PLoS One. 2019 Feb 22;14(2):e0212538. doi: 10.1371/journal.pone.0212538. eCollection 2019.
10
Wogonin inhibits cell cycle progression by activating the glycogen synthase kinase-3 beta in hepatocellular carcinoma.汉黄芩素通过激活肝肿瘤细胞中的糖原合成酶激酶-3β来抑制细胞周期进程。
Phytomedicine. 2020 Mar;68:153174. doi: 10.1016/j.phymed.2020.153174. Epub 2020 Jan 18.

引用本文的文献

1
Mechanistic Insights about Sorafenib-, Valproic Acid- and Metformin-Induced Cell Death in Hepatocellular Carcinoma.索拉非尼、丙戊酸和二甲双胍诱导肝癌细胞死亡的机制研究。
Int J Mol Sci. 2024 Feb 1;25(3):1760. doi: 10.3390/ijms25031760.
2
MiR-139-5p influences hepatocellular carcinoma cell invasion and proliferation capacities via decreasing SLITRK4 expression.miR-139-5p 通过降低 SLITRK4 表达影响肝癌细胞侵袭和增殖能力。
Biosci Rep. 2020 May 29;40(5). doi: 10.1042/BSR20193295.
3
APEX1 is a novel diagnostic and prognostic biomarker for hepatocellular carcinoma.

本文引用的文献

1
Plumbagin induces autophagy and apoptosis of SMMC-7721 cells in vitro and in vivo.白花丹素在体外和体内诱导 SMMC-7721 细胞自噬和凋亡。
J Cell Biochem. 2019 Jun;120(6):9820-9830. doi: 10.1002/jcb.28262. Epub 2018 Dec 9.
2
Involvement of the STAT5-cyclin D/CDK4-pRb pathway in β-cell proliferation stimulated by prolactin during pregnancy.妊娠期间催乳素刺激β细胞增殖涉及 STAT5-cyclin D/CDK4-pRb 通路。
Am J Physiol Endocrinol Metab. 2019 Jan 1;316(1):E135-E144. doi: 10.1152/ajpendo.00242.2018. Epub 2018 Dec 4.
3
Role of autophagy in tumorigenesis, metastasis, targeted therapy and drug resistance of hepatocellular carcinoma.
APEX1 是一种新型的肝细胞癌诊断和预后生物标志物。
Aging (Albany NY). 2020 Mar 13;12(5):4573-4591. doi: 10.18632/aging.102913.
自噬在肝癌发生、转移、靶向治疗及耐药中的作用。
World J Gastroenterol. 2018 Nov 7;24(41):4643-4651. doi: 10.3748/wjg.v24.i41.4643.
4
Synergistic antitumor effect of a γ-secretase inhibitor PF-03084014 and sorafenib in hepatocellular carcinoma.γ-分泌酶抑制剂PF-03084014与索拉非尼对肝细胞癌的协同抗肿瘤作用
Oncotarget. 2018 Oct 9;9(79):34996-35007. doi: 10.18632/oncotarget.26209.
5
Suppressor of hepatocellular carcinoma RASSF1A activates autophagy initiation and maturation.抑癌基因 RASSF1A 激活肝细胞癌的自噬起始和成熟。
Cell Death Differ. 2019 Aug;26(8):1379-1395. doi: 10.1038/s41418-018-0211-7. Epub 2018 Oct 12.
6
Sorafenib resistance in hepatocarcinoma: role of hypoxia-inducible factors.索拉非尼耐药的肝癌：缺氧诱导因子的作用。
Exp Mol Med. 2018 Oct 12;50(10):1-9. doi: 10.1038/s12276-018-0159-1.
7
Anillin is required for tumor growth and regulated by miR-15a/miR-16-1 in HBV-related hepatocellular carcinoma.在乙肝相关肝细胞癌中，膜收缩蛋白对于肿瘤生长是必需的，且受miR-15a/miR-16-1调控。
Aging (Albany NY). 2018 Aug 9;10(8):1884-1901. doi: 10.18632/aging.101510.
8
Peritumoral monocytes induce cancer cell autophagy to facilitate the progression of human hepatocellular carcinoma.肿瘤周围单核细胞诱导癌细胞自噬促进人肝癌进展。
Autophagy. 2018;14(8):1335-1346. doi: 10.1080/15548627.2018.1474994. Epub 2018 Jul 28.
9
CD24 regulates sorafenib resistance via activating autophagy in hepatocellular carcinoma.CD24 通过激活肝细胞癌中的自噬来调节索拉非尼耐药性。
Cell Death Dis. 2018 May 29;9(6):646. doi: 10.1038/s41419-018-0681-z.
10
Autophagy and liver cancer.自噬与肝癌
Turk J Gastroenterol. 2018 May;29(3):270-282. doi: 10.5152/tjg.2018.150318.