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

Abstract

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.

BCL-2 family deregulation in colorectal cancer: potential for BH3 mimetics in therapy

“…A recent study indicates a role for BOK in chemo-resistance in CRC as primary patient-derived organoids that are 5-FU resistant show decreased BOK expression compared to 5-FU sensitive organoids. This role is independent of its pro-apoptotic activity as the study shows BOK regulates uridine metabolism and thereby 5-FU chemo-conversion, thus a decrease in its expression promotes 5-FU resistance [130].…”

The Multifaceted Roles of the BCL-2 Family Member BOK

“…More than 20 years after its discovery, the role of BOK in apoptosis is not entirely understood and to some extent controversially discussed (Yakovlev et al, 2004;Jaaskelainen et al, 2010;Carpio et al, 2015;D'Orsi et al, 2016;Einsele-Scholz et al, 2016;Llambi et al, 2016;Fernandez-Marrero et al, 2017;Moldoveanu and Zheng, 2018;Schulman et al, 2019). There is increasing evidence supporting roles of BOK in cellular functions other than cell death regulation, namely, uridine metabolism and cellular proliferation (Ray et al, 2010;Moravcikova et al, 2017;Rabachini et al, 2018;Srivastava et al, 2019), autophagy (Kalkat et al, 2013), mitochondrial physiology (D'Orsi et al, 2017;Ausman et al, 2018;Schulman et al, 2019), ER homeostasis, and modulation of the UPR (Echeverry et al, 2013;Carpio et al, 2015;Schulman et al, 2016;Moravcikova et al, 2017;Kang et al, 2019). Thus, there are many open questions remaining to fully understand the different roles and functions of this protein.…”

“…So far, only a few BOK interacting partners have been described (Figure 1). Using yeast two-hybrid screens, BOK was found to interact with some selected antiapoptotic members of the BCL-2 family, i.e., MCL-1, BFL-1/BCL-2A1, and the Epstein-Barr virus BCL-2 homolog BHRF1, but neither with BCL-2, BCL-XL, or BCL-W, nor with BAX or BAK (Hsu et al, 1997;Srivastava et al, 2019). Using co-immunoprecipitation assays of Eµ-myc/Bok −/−…”

“…Recently, BOK was identified to interact with uridine monophosphate synthetase (UMPS) (Figure 1; Srivastava et al, 2019). UMPS, which in higher eukaryotes is a bifunctional enzyme consisting of the orotate phosphoribosyltransferase (OPRTase) and orotidine decarboxylase (ODCase) domains, is a central enzyme catalyzing the final steps in the de novo synthesis of orotate to uridine monophosphate (UMP) (Qumsiyeh et al, 1989).…”

“…UMPS, which in higher eukaryotes is a bifunctional enzyme consisting of the orotate phosphoribosyltransferase (OPRTase) and orotidine decarboxylase (ODCase) domains, is a central enzyme catalyzing the final steps in the de novo synthesis of orotate to uridine monophosphate (UMP) (Qumsiyeh et al, 1989). BOK binds to the ODCase domain at its dimer interface in a BH3-dependent manner (Srivastava et al, 2019). Intriguingly, it was found that, through this interaction, BOK increases the enzymatic activity of UMPS approximately threefold (Srivastava et al, 2019).…”