Kim Jong-Eun, Son Joe Eun, Jeong Hyein, Joon Kim Dong, Seo Sang Kwon, Lee Eunjung, Lim Tae Gyu, Kim Jong Rhan, Chen Hanyong, Bode Ann M, Lee Ki Won, Dong Zigang
Advanced Institutes of Convergence Technology, Seoul National University, Suwon 443-270, Republic of Korea.
Research Institute of Bio Food Industry, Institute of Green Bio Science and Technology, Seoul National University, Pyeongchang 232-916, Republic of Korea.
Cancer Res. 2015 Jul 1;75(13):2716-2728. doi: 10.1158/0008-5472.CAN-14-3655. Epub 2015 May 6.
The Pim-1 kinase regulates cell survival, proliferation, and differentiation and is overexpressed frequently in many malignancies, including leukemia and skin cancer. In this study, we used kinase profiling analysis to demonstrate that 2'-hydroxycinnamicaldehyde (2'-HCA), a compound found in cinnamon, specifically inhibits Pim-1 activity. Cocrystallography studies determined the hydrogen bonding pattern between 2'-HCA and Pim-1. Notably, 2'-HCA binding altered the apo kinase structure in a manner that shielded the ligand from solvent, thereby acting as a gatekeeper loop. Biologically, 2'-HCA inhibited the growth of human erythroleukemia or squamous epidermoid carcinoma cells by inducing apoptosis. The compound was also effective as a chemopreventive agent against EGF-mediated neoplastic transformation. Finally, 2'-HCA potently suppressed the growth of mouse xenografts representing human leukemia or skin cancer. Overall, our results offered preclinical proof of concept for 2'-HCA as a potent anticancer principle arising from direct targeting of the Pim-1 kinase.
Pim-1激酶调节细胞存活、增殖和分化，在包括白血病和皮肤癌在内的许多恶性肿瘤中经常过度表达。在本研究中，我们使用激酶谱分析来证明肉桂中发现的一种化合物2'-羟基肉桂醛（2'-HCA）特异性抑制Pim-1活性。共结晶学研究确定了2'-HCA与Pim-1之间的氢键模式。值得注意的是，2'-HCA的结合以一种将配体与溶剂隔离的方式改变了无配体激酶结构，从而起到了守门环的作用。从生物学角度来看，2'-HCA通过诱导凋亡抑制人红白血病或鳞状上皮样癌细胞的生长。该化合物作为一种化学预防剂对表皮生长因子介导的肿瘤转化也有效。最后，2'-HCA强烈抑制代表人类白血病或皮肤癌的小鼠异种移植瘤的生长。总体而言，我们的结果为2'-HCA作为一种通过直接靶向Pim-1激酶产生的强效抗癌物质提供了临床前概念验证。
