Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, 3086 Melbourne, Australia.
Institute of Pharmacology, University of Bern, Inselspital, INFO-F-603, 3010 Bern, Switzerland.
Proc Natl Acad Sci U S A. 2019 Jul 30;116(31):15469-15474. doi: 10.1073/pnas.1904523116. Epub 2019 Jul 16.
BCL-2 family proteins regulate the mitochondrial apoptotic pathway. BOK, a multidomain BCL-2 family protein, is generally believed to be an adaptor protein similar to BAK and BAX, regulating the mitochondrial permeability transition during apoptosis. Here we report that BOK is a positive regulator of a key enzyme involved in uridine biosynthesis; namely, uridine monophosphate synthetase (UMPS). Our data suggest that BOK expression enhances UMPS activity, cell proliferation, and chemosensitivity. Genetic deletion of results in chemoresistance to 5-fluorouracil (5-FU) in different cell lines and in mice. Conversely, cancer cells and primary tissues that acquire resistance to 5-FU down-regulate BOK expression. Furthermore, we also provide evidence for a role for BOK in nucleotide metabolism and cell cycle regulation. Our results have implications in developing BOK as a biomarker for 5-FU resistance and have the potential for the development of BOK-mimetics for sensitizing 5-FU-resistant cancers.
BCL-2 家族蛋白调节线粒体凋亡途径。BOK 是一种多结构域 BCL-2 家族蛋白，通常被认为是一种类似于 BAK 和 BAX 的衔接蛋白，调节凋亡过程中线粒体通透性的转变。在这里，我们报告 BOK 是参与尿苷生物合成的关键酶的正调节剂；即尿苷一磷酸合酶 (UMPS)。我们的数据表明，BOK 的表达增强了 UMPS 的活性、细胞增殖和化疗敏感性。在不同的细胞系和小鼠中， 基因缺失导致对 5-氟尿嘧啶 (5-FU) 的化疗耐药。相反，对 5-FU 产生耐药性的癌细胞和原发性组织下调 BOK 的表达。此外，我们还提供了 BOK 在核苷酸代谢和细胞周期调控中发挥作用的证据。我们的研究结果为将 BOK 作为 5-FU 耐药的生物标志物提供了依据，并为开发 BOK 模拟物以增敏 5-FU 耐药性癌症提供了可能性。
