BCL-2 family protein BOK is a positive regulator of uridine metabolism in mammals

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 Bok 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.