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

Srivastava, Rahul; Cao, Zhipeng; Nedeva, Christina; Naim, Samara; Bachmann, Daniel; Rabachini, Tatiana; Gangoda, Lahiru; Shahi, Sanjay; Glab, Jason; Menassa, Joseph; Osellame, Laura; Nelson, Tao; Fernández Marrero, Yuniel; Brown, Fiona; Wei, Andrew; Ke, Francine; O'Reilly, Lorraine; Doerflinger, Marcel; Allison, Cody; Kueh, Andrew; ... (2019). BCL-2 family protein BOK is a positive regulator of uridine metabolism in mammals. Proceedings of the National Academy of Sciences of the United States of America - PNAS, 116(31), pp. 15469-15474. National Academy of Sciences NAS 10.1073/pnas.1904523116

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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.

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