Niu Guoping, Sun Li, Pei Yunfeng, Wang Duping
Department of Clinical Laboratory, Xuzhou Central Hospital Affiliated to Southeast University, Xuzhou 221009, China.
Anticancer Agents Med Chem. 2018;18(4):583-590. doi: 10.2174/1871520617666171020124916.
Angiogenesis is a crucial process that regulated by multiple intracellular signaling pathways including MEK/ERK and JNK/SAPK. Thus, many inhibitors have developed to these pathways as anti-cancer therapeutic strategies. Oleanolic acid (OA) is a natural pentacyclic triterpenoic acid compound that present in various herbal medicines. It has been used as antitumor agent for various cancers including colorectal cancer (CRC), which attenuates angiogenesis.
To study the molecular mechanism of OA suppressing angiogenesis.
The proliferation of human umbilical vein endothelial cells (HUVECs) was determined by MTT and the invasion and migration of them were measured by wound-healing Assay, transwell migration assay and tube formation assay. The xenograft mouse model was used to study the effect of OA blocking angiogenesis in vivo. The Western blot was used to checked the phosphorylation of VEGFR2.
OA attenuates HUVECs invasion, migration, tube formation and vascular sprouting. Moreover, OA suppresses HUVECs sprout and tube formation. Importantly, OA also blocks angiogenesis in HUVECs and colorectal cancer cells (HCT-116) both in vitro and in vivo. OA-dependent suppression of tumor angiogenesis mediated by blocking the phosphorylation of the vascular endothelial growth factor receptor-2 (VEGFR2) that results in inhibition of MEK/ERK/JNK pathway.
Our results suggest that inhibition of tumor angiogenesis via the suppression VEGFR2 phosphorylation may be one of the underlying mechanisms by which OA exerts its anti-cancer effect.
血管生成是一个由包括MEK/ERK和JNK/SAPK在内的多种细胞内信号通路调控的关键过程。因此，许多针对这些通路的抑制剂已被开发出来作为抗癌治疗策略。齐墩果酸（OA）是一种存在于多种草药中的天然五环三萜酸化合物。它已被用作包括结直肠癌（CRC）在内的多种癌症的抗肿瘤药物，可减弱血管生成。
研究OA抑制血管生成的分子机制。
采用MTT法测定人脐静脉内皮细胞（HUVECs）的增殖，采用伤口愈合试验、Transwell迁移试验和管腔形成试验检测其侵袭和迁移能力。利用异种移植小鼠模型研究OA在体内阻断血管生成的作用。采用蛋白质免疫印迹法检测VEGFR2的磷酸化水平。
OA减弱HUVECs的侵袭、迁移、管腔形成和血管芽生。此外，OA抑制HUVECs的芽生和管腔形成。重要的是，OA在体外和体内均能阻断HUVECs和结肠癌细胞（HCT-116）的血管生成。OA通过阻断血管内皮生长因子受体-2（VEGFR2）的磷酸化来抑制肿瘤血管生成，从而导致MEK/ERK/JNK通路的抑制。
我们的结果表明，通过抑制VEGFR2磷酸化来抑制肿瘤血管生成可能是OA发挥抗癌作用的潜在机制之一。
