A Multi-targeted Natural Flavonoid Myricetin Suppresses Lamellipodia and Focal Adhesions Formation and Impedes Glioblastoma Cell Invasiveness and Abnormal Motility.
A Multi-targeted Natural Flavonoid Myricetin Suppresses Lamellipodia and Focal Adhesions Formation and Impedes Glioblastoma Cell Invasiveness and Abnormal Motility.
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DOI：
10.2174/1871527317666180611090006
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发表时间：
2018-08
期刊：
影响因子：
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通讯作者：
Hua-fu Zhao;G. Wang;Chang-peng Wu;Xiu-ming Zhou;Jing Wang;Zhongping Chen;S. To;Weiping Li
中科院分区：
文献类型：
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作者：
Hua-fu Zhao;G. Wang;Chang-peng Wu;Xiu-ming Zhou;Jing Wang;Zhongping Chen;S. To;Weiping Li
背景：多形性胶质母细胞瘤（GBM）是最具侵袭性和恶性的原发性脑肿瘤，其特征是快速生长并广泛浸润邻近正常脑实质，导致肿瘤复发和预后不良。杨梅素是一种天然黄酮类化合物，具有有效的抗氧化、抗炎和抗癌活性，可作为 GBM 治疗的潜在且无害的药物。方法 为了研究杨梅素的抗胶质母细胞瘤作用，单独用杨梅素或与替莫唑胺联合处理 GBM 细胞。还评估了其对 GBM 细胞运动和细胞骨架结构（包括板状伪足、粘着斑和膜皱褶）的影响。结果我们发现，单独的杨梅素可以抑制胶质母细胞瘤U-87 MG细胞的增殖、迁移和侵袭，而杨梅素和替莫唑胺的组合则没有表现出任何协同作用。对 GBM 细胞增殖的抑制作用与 PTEN 状态无关。此外，与 GBM 细胞相比，杨梅素对正常星形胶质细胞的细胞毒性较小。杨梅素可阻断板状伪足、粘着斑、膜皱褶和血管生成拟态的形成，并抑制 ROCK2、桩蛋白和皮质素的磷酸化。此外，杨梅素可以抑制 PI3K/Akt 和 JNK 信号传导，并与一系列激酶和支架蛋白结合，包括 PI3K 催化亚型（p110α、p110β 和 p110δ）、PDK1、JNK、c-Jun、ROCK2、paxillin、vinculin 和 VEcadherin。结论 总之，杨梅素是一种多靶点药物，对 GBM 细胞具有有效的抗迁移和抗侵袭作用，并抑制板状伪足和粘着斑的形成，表明它可以作为 GBM 治疗的替代选择。
BACKGROUND Glioblastoma multiforme (GBM) is the most aggressive and malignant primary brain tumor characterized by rapid growth and extensive infiltration to neighboring normal brain parenchyma, which contribute to tumor recurrence and poor prognosis. Myricetin is a natural flavonoid with potent anti-oxidant, anti-inflammatory and anti-cancer activities, which may serve as a potential and harmless agent for GBM treatment. METHODS To investigate the anti-glioblastoma effects of myricetin, GBM cells were treated with myricetin alone or in combination with temozolomide. Its effects on GBM cell motility and cytoskeletal structures including lamellipodia, focal adhesions and membrane ruffles were also evaluated. RESULTS We showed that myricetin alone inhibited glioblastoma U-87 MG cell proliferation, migration and invasion, whereas combination of myricetin and temozolomide did not exhibit any synergistic effect. The inhibitory effect on GBM cell proliferation is independent of PTEN status. Moreover, myricetin showed less cytotoxicity to normal astrocytes than GBM cells. Formation of lamellipodia, focal adhesions, membrane ruffles and vasculogenic mimicry were blocked by myricetin, and phosphorylation of ROCK2, paxillin and cortactin was suppressed. In addition, myricetin could inhibit PI3K/Akt and JNK signaling, and bind to a series of kinases and scaffold proteins including PI3K catalytic isoforms (p110α, p110β and p110δ), PDK1, JNK, c-Jun, ROCK2, paxillin, vinculin and VEcadherin. CONCLUSIONS In conclusion, myricetin is a multi-targeted drug that has potent anti-migratory and antiinvasive effects on GBM cells, and suppresses formation of lamellipodia and focal adhesions, suggesting that it may serve as an alternative option for GBM treatment.