Jin Song, Pang Rui-Ping, Shen Jing-Nan, Huang Gang, Wang Jin, Zhou Jia-Guo
Department of Orthopedic Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Apoptosis. 2007 Jul;12(7):1317-26. doi: 10.1007/s10495-007-0062-z.
Grifolin, a natural biologically active substance isolated from the edible bodies of the mushroom Albatrellus confluens, has been shown to inhibit proliferation and induce apoptosis in several cancer cell lines. But the mechanisms remain poorly understood. In this study, we investigated the apoptosis-inducing effects and the mechanisms of grifolin on human osteosarcoma cells. Our results demonstrated that grifolin induced concentration- and time-dependent suppression of proliferation and induction of apoptosis in U2OS and MG63 osteosarcoma cell lines. Grifolin induced the release of cytochrome c accompanied by activation of caspase-9, caspase-3 and cleavage of poly (ADP-ribose) polymerase (PARP). In addition, z-VAD-fmk, a universal inhibitor of caspases, prevented caspase-3 activation and PARP cleavage and inhibted grifolin-induced cell growth inhibition. Furthermore, grifolin treatment resulted in a reduction in level of phosphorylated AKT, FOXO transcription factor, and glycogen synthase kinase 3 (GSK3). Knockdown of GSK3 with siRNA inhibited the apoptotic effects of grifolin. On the other hand, grifolin treatment down-regulated the expression of the inhibitor of apoptosis protein(IAP) in both osteosarcoma cells. Taken together, our results suggested that grifolin is able to suppress the phosphorylation of Akt and its substrates FOXO transcription factor and GSK3 in osteosarcoma cells causing the suppression of proliferation and induction of mitochondria- and caspase-dependent apoptosis.
地衣酚，一种从融合白牛肝菌子实体中分离出的天然生物活性物质，已被证明能抑制多种癌细胞系的增殖并诱导其凋亡。但其机制仍知之甚少。在本研究中，我们调查了地衣酚对人骨肉瘤细胞的凋亡诱导作用及其机制。我们的结果表明，地衣酚在U2OS和MG63骨肉瘤细胞系中诱导了浓度和时间依赖性的增殖抑制和凋亡诱导。地衣酚诱导细胞色素c的释放，同时激活半胱天冬酶-9、半胱天冬酶-3并切割聚（ADP-核糖）聚合酶（PARP）。此外，半胱天冬酶的通用抑制剂z-VAD-fmk可阻止半胱天冬酶-3的激活和PARP的切割，并抑制地衣酚诱导的细胞生长抑制。此外，地衣酚处理导致磷酸化AKT、FOXO转录因子和糖原合酶激酶3（GSK3）水平降低。用小干扰RNA敲低GSK3可抑制地衣酚的凋亡作用。另一方面，地衣酚处理下调了两种骨肉瘤细胞中凋亡抑制蛋白（IAP）的表达。综上所述，我们的结果表明，地衣酚能够抑制骨肉瘤细胞中Akt及其底物FOXO转录因子和GSK3的磷酸化，从而导致增殖抑制以及线粒体和半胱天冬酶依赖性凋亡的诱导。
