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一种与海洋海绵相关的真菌代谢产物莫纳可林X通过下调VEGFR2信号传导来抑制血管生成。

A marine sponge associated fungal metabolite monacolin X suppresses angiogenesis by down regulating VEGFR2 signaling.

作者信息

Nagabhishek Sirpu Natesh, Madan Kumar Arumugam, B Sambhavi, Balakrishnan Anandan, Katakia Yash T, Chatterjee Suvro, Nagasundaram Nagarajan

机构信息

Cancer Biology Lab, Molecular and Nanomedicine Research Unit, Sathyabama Institute of Science and Technology Chennai-600 119 Tamil Nadu India

Department of Genetics, Dr ALM PGIBMS University of Madras Taramani Chennai Tamil Nadu India.

出版信息

RSC Adv. 2019 Aug 27;9(46):26646-26667. doi: 10.1039/c9ra05262c. eCollection 2019 Aug 23.

DOI:10.1039/c9ra05262c
PMID:35528587
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9070443/
Abstract

Cancer is one of the leading causes of global death and there is an urgent need for the development of cancer treatment; targeting VEGFR2 could be one of the promising therapies. In the present study, previously isolated marine fungal metabolite monacolin X, suppresses angiogenic characteristics such as proliferation, migration, adhesion, invasion and tube formation of HUVECs when stimulated by VEGF, at a non-toxic concentration. Monacolin X downregulated VEGFR2, PKCα and PKCη mRNA expression. Further, monacolin X inhibited angiogenesis in CAM assay, vascular sprouting in aortic ring, decreased ISV and SIV length and diameter in Tg (Kdr:EGFP)/ko1 zebrafish embryos. Monacolin X showed reduced protein expression of pVEGFR2, pAKT1, pMAPKAPK2, pFAK and pERK1 in breast cancer lines and in DMBA induced mammary carcinoma in SD rats showed tumor regression and anti-angiogenesis ability decrease pVEGFR2 and pAKT1 protein expression. studies also revealed monacolin X ability to bind to crucial amino acid Cys 919 in the active site of VEGFR2 suggesting it to be a potent VEGFR2 inhibitor.

摘要

癌症是全球主要死因之一，迫切需要开发癌症治疗方法；靶向血管内皮生长因子受体2（VEGFR2）可能是一种有前景的治疗方法。在本研究中，先前分离出的海洋真菌代谢产物莫纳可林X，在无毒浓度下，可抑制人脐静脉内皮细胞（HUVECs）在血管内皮生长因子（VEGF）刺激下的增殖、迁移、黏附、侵袭和管腔形成等血管生成特性。莫纳可林X下调了VEGFR2、蛋白激酶Cα（PKCα）和蛋白激酶Cη（PKCη）的mRNA表达。此外，莫纳可林X在鸡胚绒毛尿囊膜试验中抑制血管生成，在主动脉环试验中抑制血管芽生，减少转基因（Kdr:EGFP）/ko1斑马鱼胚胎中的节间血管（ISV）和背侧纵行血管（SIV）的长度和直径。莫纳可林X在乳腺癌细胞系中显示磷酸化VEGFR2（pVEGFR2）、磷酸化蛋白激酶B1（pAKT1）、磷酸化丝裂原活化蛋白激酶激活的蛋白激酶2（pMAPKAPK2）、磷酸化黏着斑激酶（pFAK）和磷酸化细胞外信号调节激酶1（pERK1）的蛋白表达降低，在二甲基苯并蒽（DMBA）诱导的SD大鼠乳腺癌中显示肿瘤消退和抗血管生成能力，降低pVEGFR2和 pAKT1蛋白表达。研究还揭示了莫纳可林X与VEGFR2活性位点关键氨基酸半胱氨酸919结合的能力，表明它是一种有效的VEGFR2抑制剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/76e9/9070443/0a82a79f1460/c9ra05262c-f11.jpg
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