Lu Pei-Hua, Chen Min-Bin, Liu Yuan-Yuan, Wu Mian-Hua, Li Wen-Ting, Wei Mu-Xin, Liu Chao-Ying, Qin Shu-Kui
Department of Medical Oncology, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China.
Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine (TCM) Prevention and Treatment of Tumor of Nanjing University of Chinese Medicine, Nanjing, China.
Oncotarget. 2017 Apr 4;8(14):22800-22810. doi: 10.18632/oncotarget.15205.
Hepatocellular carcinoma (HCC) is a highly aggressive neoplasm. We aim to explore the anti-HCC activity by a natural prenylflavonoid icaritin. Icaritin was cytotoxic and pro-apoptotic when added to established (HepG2, KYN-2 and Huh-7 lines) and primary human HCC cells. At the signaling level, icaritin inhibited sphingosine kinase 1 (SphK1) activity in HCC cells, which led to pro-apoptotic ceramide production and JNK1 activation. SphK1 inhibition or silence (by shRNA/microRNA) mimicked icaritin-mediated cytotoxicity, and almost nullified icaritin's activity in HepG2 cells. Reversely, exogenous over-expression of SphK1 sensitized icaritin-induced HepG2 cell apoptosis. In vivo, oral administration of icaritin dramatically inhibited HepG2 xenograft growth in SCID mice. Further, SphK1 activity in icaritin-treated tumors was largely inhibited. In summary, icaritin exerts potent anti-HCC activity in vitro and in vivo. SphK1 inhibition could be the primary mechanism of its actions in HCC cells.
肝细胞癌（HCC）是一种侵袭性很强的肿瘤。我们旨在探索天然异戊烯基黄酮类化合物淫羊藿素的抗HCC活性。当将淫羊藿素添加到已建立的（HepG2、KYN-2和Huh-7细胞系）及原代人HCC细胞中时，它具有细胞毒性并能促进细胞凋亡。在信号传导水平上，淫羊藿素抑制HCC细胞中的鞘氨醇激酶1（SphK1）活性，这导致促凋亡的神经酰胺生成和JNK1激活。SphK1抑制或沉默（通过短发夹RNA/微小RNA）模拟了淫羊藿素介导的细胞毒性，并且几乎消除了淫羊藿素在HepG2细胞中的活性。相反，SphK1的外源性过表达使淫羊藿素诱导的HepG2细胞凋亡更加敏感。在体内，口服淫羊藿素显著抑制了SCID小鼠中HepG2异种移植瘤的生长。此外，淫羊藿素处理的肿瘤中的SphK1活性被很大程度地抑制。总之，淫羊藿素在体外和体内均发挥强大的抗HCC活性。SphK1抑制可能是其在HCC细胞中发挥作用的主要机制。
