Putt Karson S, Chen Grace W, Pearson Jennifer M, Sandhorst Joseph S, Hoagland Martin S, Kwon Jung-Taek, Hwang Soon-Kyung, Jin Hua, Churchwell Mona I, Cho Myung-Haing, Doerge Daniel R, Helferich William G, Hergenrother Paul J
Department of Biochemistry, University of Illinois, Urbana, Illinois 61801, USA.
Nat Chem Biol. 2006 Oct;2(10):543-50. doi: 10.1038/nchembio814. Epub 2006 Aug 27.
Mutation and aberrant expression of apoptotic proteins are hallmarks of cancer. These changes prevent proapoptotic signals from being transmitted to executioner caspases, thereby averting apoptotic death and allowing cellular proliferation. Caspase-3 is the key executioner caspase, and it exists as an inactive zymogen that is activated by upstream signals. Notably, concentrations of procaspase-3 in certain cancerous cells are significantly higher than those in noncancerous controls. Here we report the identification of a small molecule (PAC-1) that directly activates procaspase-3 to caspase-3 in vitro and induces apoptosis in cancerous cells isolated from primary colon tumors in a manner directly proportional to the concentration of procaspase-3 inside these cells. We found that PAC-1 retarded the growth of tumors in three different mouse models of cancer, including two models in which PAC-1 was administered orally. PAC-1 is the first small molecule known to directly activate procaspase-3 to caspase-3, a transformation that allows induction of apoptosis even in cells that have defective apoptotic machinery. The direct activation of executioner caspases is an anticancer strategy that may prove beneficial in treating the many cancers in which procaspase-3 concentrations are elevated.
凋亡蛋白的突变和异常表达是癌症的标志。这些变化阻止促凋亡信号传递给执行凋亡的半胱天冬酶，从而避免凋亡死亡并使细胞增殖。半胱天冬酶-3是关键的执行凋亡的半胱天冬酶，它以无活性的酶原形式存在，可被上游信号激活。值得注意的是，某些癌细胞中半胱天冬酶原-3的浓度显著高于非癌细胞对照。在此，我们报告了一种小分子（PAC-1）的鉴定，它在体外可直接将半胱天冬酶原-3激活为半胱天冬酶-3，并以与这些细胞内半胱天冬酶原-3浓度成正比的方式诱导从原发性结肠肿瘤分离的癌细胞凋亡。我们发现PAC-1可延缓三种不同癌症小鼠模型中的肿瘤生长，其中包括两种口服PAC-1的模型。PAC-1是已知的首个可直接将半胱天冬酶原-3激活为半胱天冬酶-3的小分子，这种转变即使在凋亡机制有缺陷的细胞中也能诱导凋亡。直接激活执行凋亡的半胱天冬酶是一种抗癌策略，可能对治疗许多半胱天冬酶原-3浓度升高的癌症有益。
