期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 31, 页码 15469-15474出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1904523116
关键词
Bok; apoptosis; UMPS; chemoresistance; metabolism
资金
- Swiss National Science Foundation [31003A_173006]
- La Trobe University
- Graduate School of Cellular and Biomedical Sciences of the University of Bern
- La Trobe University Research Focus Area
- Swiss National Science Foundation (SNF) [31003A_173006] Funding Source: Swiss National Science Foundation (SNF)
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.
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