Institute of Biochemistry and Biotechnology, School of Applied Chemistry, Chung Shan Medical University, and Department of Pathology, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC.
Oncol Rep. 2011 Feb;25(2):583-91. doi: 10.3892/or.2010.1097. Epub 2010 Dec 10.
Quercetin, a naturally occurring flavonoid abundant in fruits and vegetables, has been demonstrated as a multipotent bioflavonoid with great potential for the prevention and treatment of cancer. Apoptosis is thought to be an important response to most chemotherapeutic agents in leukemia cells. However, the underlying mechanism of induction of apoptosis by quercetin involving epigenetic regulation is poorly understood. In the present study, by evaluation of fragmentation of DNA, poly (ADP-ribose) polymerase (PARP) and procaspases, we found that quercetin was able to induce apoptosis of human leukemia HL-60 cells in a dose-dependent manner. Quercetin triggered the extrinsic apoptosis pathway through activation of caspase-8 and induction of Bid cleavage, Bax conformation change and cytochrome c release. Furthermore, quercetin induced Fas ligand (FasL) expression involving activation of the extracellular signal-regulated kinase (ERK) and Jun N-terminus kinase (JNK) signaling pathways. In addition to activation of c-Jun, quercetin increased histone H3 acetylation which resulted in the promotion of the expression of FasL. Quercetin exhibited potential for the activation of histone acetyltransferase (HAT) and the inhibition of histone deacetyltransferase (HADC), both of which contributed to histone acetylation. However, only the activation effect on HAT was associated with the ERK and JNK pathway. These results demonstrated that quercetin induced FasL-related apoptosis by transactivation through activation of c-jun/AP-1 and promotion of histone H3 acetylation in HL-60 cells.
槲皮素是一种天然存在的类黄酮，广泛存在于水果和蔬菜中，具有多效生物类黄酮的特性，在癌症的预防和治疗方面具有巨大潜力。细胞凋亡被认为是白血病细胞对大多数化疗药物的重要反应。然而，槲皮素通过表观遗传调控诱导细胞凋亡的潜在机制尚不清楚。在本研究中，通过评估 DNA 的片段化、多聚（ADP-核糖）聚合酶（PARP）和 procaspases，我们发现槲皮素能够以剂量依赖的方式诱导人白血病 HL-60 细胞凋亡。槲皮素通过激活 caspase-8 并诱导 Bid 切割、Bax 构象改变和细胞色素 c 释放来触发外源性凋亡途径。此外，槲皮素诱导 Fas 配体（FasL）表达，涉及细胞外信号调节激酶（ERK）和 Jun N 端激酶（JNK）信号通路的激活。除了激活 c-Jun 外，槲皮素还增加了组蛋白 H3 的乙酰化，从而促进 FasL 的表达。槲皮素具有激活组蛋白乙酰转移酶（HAT）和抑制组蛋白去乙酰化酶（HADC）的潜力，这两者都有助于组蛋白乙酰化。然而，只有对 HAT 的激活作用与 ERK 和 JNK 通路有关。这些结果表明，槲皮素通过激活 c-jun/AP-1 的转激活作用，并促进 HL-60 细胞组蛋白 H3 的乙酰化，诱导 FasL 相关的凋亡。
