Institute of Biochemistry, College of Life Science, National Chung Hsing University, Taichung, Taiwan.
J Agric Food Chem. 2010 Sep 8;58(17):9511-7. doi: 10.1021/jf1019533.
Glioblastoma multiforme (GBM) is the most common and lethal type of primary brain tumor. Despite recent therapeutic advances in other cancers, the treatment of GBM remains ineffective and essentially palliative. The current focus lies in the finding of components that activate the AMP-activated protein kinase (AMPK), one key enzyme thought to be activated during the caloric restriction (CR). In the present study, we found that treatment of hispidulin, a flavone isolated from Saussurea involucrate Kar. et Kir., resulted in dose-dependent inhibition of GBM cellular proliferation. Interestingly, we show that hispidulin activated AMPK in GBM cells. The activation of AMPK suppressed downstream substrates, such as the mammalian target of rapamycin (mTOR) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), and resulted in a general decrease in mRNA translation. Moreover, hispidulin-activated AMPK decreases the activity and/or expression of lipogenic enzymes, such as fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC). Furthermore, hispidulin blocked the progression of the cell cycle at the G1 phase and induced apoptosis by inducing p53 expression and further upregulating p21 expression in GBM cells. On the basis of these results, we demonstrated that hispidulin has the potential to be a chemopreventive and therapeutic agent against human GBM.
多形性胶质母细胞瘤（GBM）是最常见和最致命的原发性脑肿瘤。尽管近年来在其他癌症的治疗方面取得了进展，但 GBM 的治疗仍然无效，基本上只是姑息性的。目前的重点在于寻找激活 AMP 激活的蛋白激酶（AMPK）的成分，AMPK 被认为是在热量限制（CR）期间被激活的关键酶之一。在本研究中，我们发现从雪莲中分离出的一种黄酮类化合物糙苏素能剂量依赖性地抑制 GBM 细胞的增殖。有趣的是，我们表明糙苏素能在 GBM 细胞中激活 AMPK。AMPK 的激活抑制了下游底物，如雷帕霉素靶蛋白（mTOR）和真核起始因子 4E 结合蛋白 1（4E-BP1），导致 mRNA 翻译普遍减少。此外，糙苏素激活的 AMPK 降低了脂肪酸合酶（FASN）和乙酰辅酶 A 羧化酶（ACC）等脂肪生成酶的活性和/或表达。此外，糙苏素通过诱导 p53 表达并进一步上调 GBM 细胞中的 p21 表达，阻断细胞周期在 G1 期的进展并诱导细胞凋亡。基于这些结果，我们证明糙苏素有潜力成为针对人类 GBM 的化学预防和治疗药物。
