Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
Neoplasia. 2011 Sep;13(9):854-63. doi: 10.1593/neo.11594.
Increasing evidence suggests that FOXO1 possesses a tumor suppressor function. Inactivation of FOXO1 has been documented in many types of human cancer, and restoring the activity of FOXO1 holds promise for cancer treatment. In this study, we identified a FOXO1-derived peptide termed FO1-6nls that inhibits cyclin-dependent kinases 1 and 2 (CDK1/2)-mediated phosphorylation of FOXO1 at the serine 249 residue in vitro and in vivo. Overexpression of FO1-6nls in prostate cancer (PCa) cells not only blocked CDK1-induced cytoplasmic localization of FOXO1 but also augmented FOXO1's transcriptional activity. This effect of FO1-6nls requires its binding to CDK1 and CDK2. Moreover, the ectopic expression of FO1-6nls inhibited the growth of PTEN-positive DU145 PCa cells. Importantly, the growth-inhibitory function of FO1-6nls is dependent on FOXO1. Finally, the ectopic expression of FO1-6nls overcame CDK1-mediated inhibition of FOXO1-induced apoptosis of PCa cells. These results indicate that the FOXO1-derived peptide FO1-6nls can restore FOXO1's tumor suppressor function by specifically opposing CDK1/2-mediated phosphorylation and inhibition of FOXO1 and hence may have a therapeutic potential for the treatment of PCa.
越来越多的证据表明 FOXO1 具有肿瘤抑制功能。FOXO1 的失活已在许多人类癌症类型中得到证实，恢复 FOXO1 的活性有望用于癌症治疗。在这项研究中，我们鉴定了一种称为 FO1-6nls 的 FOXO1 衍生肽，它可在体外和体内抑制 CDK1/2 介导的 FOXO1 丝氨酸 249 残基磷酸化。FO1-6nls 在前列腺癌细胞中的过表达不仅阻止了 CDK1 诱导的 FOXO1 细胞质定位，而且增强了 FOXO1 的转录活性。FO1-6nls 的这种作用需要其与 CDK1 和 CDK2 结合。此外，FO1-6nls 的异位表达抑制了 PTEN 阳性的 DU145 前列腺癌细胞的生长。重要的是，FO1-6nls 的生长抑制功能依赖于 FOXO1。最后，FO1-6nls 的异位表达克服了 CDK1 介导的对 FOXO1 诱导的前列腺癌细胞凋亡的抑制作用。这些结果表明，FOXO1 衍生肽 FO1-6nls 可以通过特异性拮抗 CDK1/2 介导的 FOXO1 磷酸化和抑制来恢复 FOXO1 的肿瘤抑制功能，因此可能具有治疗前列腺癌的治疗潜力。
