Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School Boston, MA 02215, USA.
Center for Cognition and Sociality Institute for Basic Science, Daejeon 34126, Republic of Korea.
Am J Chin Med. 2021;49(3):767-784. doi: 10.1142/S0192415X21500361. Epub 2021 Mar 3.
Gliomas are the mostly observed form of primary brain tumor, and glioblastoma multiforme (GBM) shows the highest incidence. The survival rate of GBM is fairly poor; thus, discovery of effective treatment options is required. Among several suggested targets for therapy, the Axl/IL-6/STAT3 signaling pathway has gained recent interest because of its important role within cancer microenvironment. Quercetin, a plant flavonoid, is well known for its anticancer action. However, the effect of quercetin on Axl has never been reported. Quercetin treatment significantly reduced cell viability in two GBM cell lines of U87MG and U373MG while keeping 85% of normal astrocytes alive. Further western blot assays suggested that quercetin induces apoptosis but does not affect Akt or mitogen-activated protein kinases, factors related to cell proliferation. Quercetin also decreased IL-6 release and phosphorylation of STAT3 in GBM cells. In addition, gene expression, protein expression, and half-life of synthesized Axl protein were all suppressed by quercetin. By applying shRNA for knockdown of Axl, we could confirm that the role of Axl was crucial in the apoptotic effect of quercetin on GBM cells. In conclusion, we suggest quercetin as a potential anticancer agent, which may improve cancer microenvironment of GBM via the Axl/IL-6/STAT3 pathway.
神经胶质瘤是原发性脑肿瘤中最常见的类型，其中多形性胶质母细胞瘤（GBM）的发病率最高。GBM 的存活率相当低，因此需要寻找有效的治疗方法。在几种被提议的治疗靶点中，Axl/IL-6/STAT3 信号通路由于其在癌症微环境中的重要作用而受到了最近的关注。槲皮素是一种植物类黄酮，因其抗癌作用而广为人知。然而，槲皮素对 Axl 的作用从未被报道过。槲皮素治疗显著降低了 U87MG 和 U373MG 两种 GBM 细胞系的细胞活力，同时保持 85%的正常星形胶质细胞存活。进一步的 Western blot 分析表明，槲皮素诱导细胞凋亡，但不影响 Akt 或丝裂原活化蛋白激酶（与细胞增殖有关的因子）。槲皮素还降低了 GBM 细胞中 IL-6 的释放和 STAT3 的磷酸化。此外，槲皮素抑制了 Axl 基因表达、蛋白表达和合成 Axl 蛋白的半衰期。通过应用 Axl 的 shRNA 进行敲低，我们可以证实 Axl 在槲皮素对 GBM 细胞的凋亡作用中起着关键作用。总之，我们认为槲皮素是一种有潜力的抗癌药物，它可能通过 Axl/IL-6/STAT3 通路改善 GBM 的癌症微环境。
