4′-hydroxywogonin inhibits colorectal cancer angiogenesis by disrupting PI3K/AKT signaling
4′-hydroxywogonin inhibits colorectal cancer angiogenesis by disrupting PI3K/AKT signaling
复制标题
4-羟基汉黄芩素通过破坏 PI3K/AKT 信号传导抑制结直肠癌血管生成
DOI：
10.1016/j.cbi.2018.09.003
复制
发表时间：
2018-12-25
影响因子：
5.1
通讯作者：
Cheng, Haibo
中科院分区：
文献类型：
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作者：
Sun, Dongdong;Zhang, Feng;Cheng, Haibo
血管生成是实体瘤生长和转移的基础，抗血管生成治疗已成为肿瘤治疗的重要治疗选择。结直肠癌（CRC）是全球癌症相关死亡的第四大原因。本研究旨在探讨天然化合物4 '-羟基汉黄芩素（4'-HW）对CRC相关血管生成的抑制作用。培养人CRC细胞系SW 620细胞和正常人肠上皮HIEC细胞，并用白细胞介素-6处理以模拟肿瘤炎症微环境。我们的数据表明，4 '-HW以浓度和时间依赖性方式降低SW 620细胞的存活率。4 '-HW对SW 620细胞的增殖也有抑制作用，但对HIEC细胞的活力影响不大。此外，4 '-HW浓度依赖性地降低血管内皮生长因子-A（VEGF-A）的mRNA和蛋白表达，VEGF-A是肿瘤血管生成中的主要促血管生成细胞因子。随后，4 '-HW浓度依赖性地抑制磷脂酰肌醇3-激酶（PI 3 K）和AKT的磷酸化。PI 3 K抑制剂wortmannin与4 '-HW作用相似，能显著下调SW 620细胞VEGF-A的表达，wortmannin与4'-HW联合作用更明显。最后，用4 '-HW处理的SW 620细胞的条件培养基孵育的人脐静脉内皮细胞（HUVEC）在Matrigel上表现出受损的血管生成能力。单独与抗VEGF-A中和抗体孵育也抑制了体外HUVEC的血管生成特性。总的来说，4 '-HW降低了CRC中的活力并减少了血管生成，这与通过破坏PI 3 K/AKT途径下调VEGF-A表达有关。我们的发现表明4 '-HW是一种有前途的针对CRC的抗癌剂，靶向血管生成。
Angiogenesis is fundamental for solid tumor growth and metastasis, and anti-angiogenic therapy has been an important therapeutic option for cancer treatment. Colorectal cancer (CRC) represents the fourth leading cause of cancer-related death worldwide. The current studies were aimed at investigating the anti-angiogenic effects of the natural compound 4'-hydroxywogonin (4'-HW) on CRC-related angiogenesis. Human CRC cell line SW620 cells and normal human intestinal epithelial HIEC cells were cultured and treated with interleukin-6 to mimic the tumor inflammatory microenvironment. Our data showed that 4'-HW reduced the viability of SW620 cells in a concentration- and time-dependent manner. 4'-HW also suppressed the proliferation of SW620 cells, but had little effect on the viability of HIEC cells. Moreover, 4'-HW concentration-dependently decreased the mRNA and protein expression of vascular endothelial growth factor-A (VEGF-A), the predominant pro-angiogenic cytokine in tumor angiogenesis. Subsequently, 4'-HW concentration-dependently inhibited the phosphorylation of phosphatidylinositol 3-kinase (PI3K) and AKT. PI3K inhibitor wortmannin, similar to 4'-HW, significantly downregulated the VEGF-A expression in SW620 cells, and combination of wortmannin and 4'-HW produced more significant effects. Finally, human umbilical vein endothelial cells (HUVECs) incubated with the conditioned medium of 4'-HW-treated SW620 cells exhibited impaired angiogenic capacity at Matrigel. Incubation with the neutralizing antibody against VEGF-Aalone also suppressed the angiogenic properties of HUVECs in vitro. Collectively, 4'-HW decreased the viability and reduced angiogenesis in CRC, which was associated with downregulation of VEGF-A expression by disrupting the PI3K/AKT pathway. Our discoveries suggested 4'-HW as a promising anticancer agent against CRC targeting angiogenesis.