Role of NUDT5 in Breast Cancer

NUDT5 (NUDIX hydrolase 5 or NUDIX5) 

        The Nudix hydrolase superfamily plays a crucial role in cellular 'housekeeping' by catalyzing the hydrolysis of Nucleoside Diphosphates linked to various moieties ("X"). Among its members, NUDT5 is responsible for the hydrolysis of mono (ADP-ribose) (mADPr), converting it to ribose-5-phosphate and adenosine-monophosphate (AMP). Under specific conditions, NUDT5 can also convert mADPr to ATP. The breakdown of such diphosphate-containing compounds, including ADPr, is essential, as ADPr accumulation in cells can have cytotoxic effects. This includes altering calcium entry into cells, influencing membrane depolarization, serving as a neurotransmitter in primate and murine colons, and spontaneously modifying proteins. Without Nudix hydrolase activity, free ADPr would accumulate during the breakdown of Poly (ADP-ribose) (PAR), as a byproduct of tRNA synthesis, following NAD+ glycohydrolysis, after deacetylation of O-acetyl-ADPr, or through the breakdown of the signaling molecule cyclic ADPr.NUDT5 plays a significant role in breast cancer progression. It is involved in the growth of breast cancer stem cells (BCSCs), which are known to initiate epithelial-to-mesenchymal transition (EMT), metastatic colonization, and growth. 

    NUDT5 is essential for BCSC generation and maintenance. It is highly expressed in circulating tumor cells (CTCs) and is associated with increased levels of recurrence and metastasis in patients. Additionally, NUDT5 is implicated in angiogenesis, as suggested by gene expression changes occurring in BCSCs in 3D cell culture. Overall, NUDT5 is a potential therapeutic target for aggressive hormone receptor-positive (HR+) breast cancers. NUDT5 plays a role in the metabolism of ADP-ribose and 8-oxo-guanine and has recently been recognized as a regulator of hormone-dependent gene expression and proliferation in breast cancer cells. 

            Figure: NUDT5 3D Structure

    The NUDIX enzymes, despite being highly conserved across organisms, have elusive biological roles and biochemical redundancies, participating in cellular metabolism, homeostasis, and mRNA processing. The NUDT enzymes play a significant role in the progression of breast cancer. Studies have shown that certain members of the NUDT enzyme family, such as NUDT1, NUDT2, NUDT5, and NUDT16, are upregulated in breast tumor tissue compared to normal tissue. Elevated levels of these enzymes are associated with poorer overall survival in hormone receptor-positive breast cancer patients. Inhibition of NUDT1 and NUDT2 has shown promise as a potential therapeutic target, as it reduces breast cancer cell growth and metastatic pathways. Further research is needed to fully understand the signaling pathways and mechanisms by which NUDT enzymes contribute to breast cancer progression. The NUDT (Nudix) enzymes play a significant role in breast cancer progression. Specifically, the enzyme NUDT5 has been shown to be essential for the growth of hormone receptor-positive (HR+) breast cancer and the initiation and maintenance of breast cancer stem cells (BCSCs). BCSCs are known to drive metastasis, epithelial-to-mesenchymal transition (EMT), and tumor growth. In addition to NUDT5, other members of the NUDT enzyme family, such as NUDT1, NUDT2, and NUDT16, have been found to be overexpressed in breast tumors and associated with poor overall survival in HR+ breast cancer patients. These findings suggest that NUDT enzymes could serve as potential therapeutic targets for aggressive HR+ breast cancers. Further research is needed to fully understand the role of other NUDT family members, such as NUDT4, NUDT13, and NUDT21, in breast cancer progression. 

    The current focus of research on targeting NUDT enzymes in breast cancer treatment is to develop selective inhibitors for specific NUDT enzymes, such as NUDT1 and NUDT5, which have shown efficacy in inhibiting breast cancer cell growth in vitro and in vivo. These inhibitors have the potential to be used as therapeutic agents for breast cancer patients. Additionally, there is ongoing research to understand the signaling pathways and mechanisms through which NUDT enzymes contribute to breast cancer progression. 

    Integration of global omic datasets, such as phosphoproteomic and gene expression data, is being explored to gain a better understanding of the role of NUDT enzymes and identify novel biomarkers and drug discovery targets for aggressive hormone receptor-positive breast cancers and other cancer types. Existing therapies or drugs that specifically target NUDT enzymes in breast cancer include NUDT1-selective inhibitors and NUDT5-selective inhibitors. NUDT1-selective inhibitors have shown efficacy in multiple studies in vitro and in vivo. Inhibition of NUDT1 (MTH1) has been shown to reduce breast cancer cell growth in vitro and in vivo. NUDT5-selective inhibitor TH1457 has been found to block cell proliferation in breast cancer cells. These inhibitors hold promise as potential therapeutic options for the management of breast cancer patients. 

Reference

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2. Page, B. D., Valerie, N. C., Wright, R. H., Wallner, O., Isaksson, R., Carter, M., ... & Helleday, T. (2018). Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells. Nature communications, 9(1), 250. 

3. Pickup, K. E., Pardow, F., Carbonell-Caballero, J., Lioutas, A., Villanueva-Cañas, J. L., Wright, R. H., & Beato, M. (2019). Expression of oncogenic drivers in 3D cell culture depends on nuclear ATP synthesis by NUDT5. Cancers, 11(9), 1337. 

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5. Zhang, H., Zhang, L. Q., Yang, C. C., Li, J., Tian, X. Y., Li, D. N., ... & Cai, J. P. (2021). The high expression of NUDT5 indicates poor prognosis of breast cancer by modulating AKT/Cyclin D signaling. Plos one, 16(2), e0245876. 5. Wright, R. H., & Beato, M. (2021). Role of the NUDT enzymes in breast cancer. International Journal of Molecular Sciences, 22(5), 2267.