J Cell Sci：癌症热疗研究获新突破

肿瘤热疗，或称加温治癌、温热治癌、高温治癌等，是用加热方法治疗肿瘤，近20年来获迅速发展，在临床上已显出很好的效果。大量的临床研究表明，热疗合并放疗或/和化疗的效果，有明显的互补和增效作用；肿瘤热疗若使用得当，对某些肿瘤治疗的全消率可提高一倍左右，且无毒副作用，远期疗效也很可观。虽然热疗正越来越广泛的应用，但其中基本分子机制目前仍不清楚。

近日，班戈大学的研究人员确定了细胞中存在一种“开关”可以帮助热杀死肿瘤。该开关机制可以有效的将热量和一种破坏基因的抗癌药物结合起来治疗前列腺癌等。这种新疗法的背后机制是热量关闭细胞的基本生存能力。

这项最新研究发表在Journal of Cell Science杂志上，研究发现热量通过促进产生一种新的蛋白质调节细胞的生存系统。有趣的是，这种蛋白质只在温度升高激活一种基因时才会生成。

编译自：How heat helps to treat cancer

doi:10.1242/​jcs.104075
PMC:
PMID:

Heat induction of a novel Rad9 variant from a cryptic translation initiation site reduces mitotic commitment

Simon Janes, Ulrike Schmidt, Karim Ashour Garrido, Nadja Ney, et al.

Exposure of human cells to heat switches DNA damage signaling from genotoxic to temperature stress. This change reduces mitotic commitment at the expense of DNA break repair. The thermal alterations behind this switch remain elusive despite the successful use of heat to sensitize cancer cells to DNA breaks. Rad9 is a highly conserved subunit of the Rad9-Rad1-Hus1 (9-1-1) checkpoint-clamp that is loaded by Rad17 onto damaged chromatin. At the DNA, Rad9 activates the checkpoint kinases Rad3^ATR and Chk1 to arrest cells in G2. Using Schizosaccharomyces pombe as a model eukaryote, we discovered a new variant of Rad9, Rad9-M50, expression of which is specifically induced by heat. High temperatures promote alternative translation from a cryptic initiation codon at methionine-50. This process is restricted to cycling cells and independent of the temperature-sensing MAP kinase pathway. While full-length Rad9 delays mitosis in the presence of DNA lesions, Rad9-M50 functions in a remodeled checkpoint pathway to reduce mitotic commitment at elevated temperatures. This remodeled pathway still relies on Rad1 and Hus1, but acts independently of Rad17. Heat-induction of Rad9-M50 ensures that Chk1 kinase remains in a hypo-phosphorylated state. Elevated temperatures specifically reverse the DNA damage-induced modification of Chk1 in a manner dependent on Rad9-M50. Taken together, heat reprograms the DNA damage checkpoint at the level of Chk1 by inducing a Rad9 variant that can act outside of the canonical 9-1-1 complex.

(责任编辑：yuezhiqiang)