NUDT5 is found to be overexpressed in certain cancers in humans
Could NUDT5 inhibitors lead to new cancer treatments? NUDIX hydrolases are a superfamily of enzymes are found in all classes of organisms and are responsible for hydrolyzing modified nucleoside diphosphates. One of the most well-studied NUDIX hydrolases is NUDT1 (also known as MTH1); it has been found to be associated with several diseases such as Parkinson’s disease and cancers1. However, another member of the superfamily, NUDT5, has recently gathered some attention for its association with certain cancers in humans. NUDT5 hydrolyses substrates such as 8-OH-dGDP, 8-OH-dADP, and ADP-ribose (ADPR)2.
A recent study reported that high levels MTH1 and NUDT5 were observed in non-small-cell-lung cancer (NSCLC) cell lines and tissues and that higher levels of both proteins in NSCLC patients were associated with tumor metastasis and poorer prognosis3. Another new study published in PLOS ONE showed that NUDT5 expression was upregulated in human breast cancer cell lines and breast tumor tissues. The researchers also made the startling discovery that breast cancer patients with high NUDT5 expression profiles had a drastically poorer outcome than those with a lower NUDT5 expression profile4.
NUDT5 promotes carcinogenesis of breast cancer cells
The function of NUDT5 in regulating cellular proliferation was apparent when suppressing NUDT5 expression in some breast cancer cell lines dramatically reduced growth, migration, and invasiveness of the cancer cells4. NUDT5 also increases the aggressiveness of breast cancer and function as a key regulator of several oncogenic pathways5. Additionally, because NUDT5 aids in the production of nuclear ATP (energy), NUDT5 is important in ATP-dependent cellular processes such as chromatin remodeling, proliferation, and transcriptional regulation induced by estrogen in breast cancers. Thus, NUDT5 seems to play a profound role in promoting the carcinogenesis of breast cancers. This prompted several researchers to explore the idea of utilizing NUDT5 inhibitors to specifically target and inhibit NUDT5 to impede the carcinogenesis of breast cancer cells.
NUDT5 inhibitors are new potential anti-cancer drugs
A group of researchers at the Karolinska Institutet of Sweden have recently identified several potent NUDT5 inhibitors which are able to optimally target the protein6. The NUDT5 inhibitors were stifling nuclear ATP production, estrogen signaling, and cell proliferation of breast cancer cells and thus, may potentially be a promising treatment option for breast cancers6. More studies are required to further validate the safety and efficacy of using NUDT5 inhibitors to treat breast cancers, especially breast cancer patients who have high NUDT5 expression profiles.
Learn more about using a Transcreener Assay to detect NUDT5 enzymatic activity.
- McLennan, A. G. The Nudix hydrolase superfamily. Cell. Mol. Life Sci. 63, 123–143 (2006). https://link.springer.com/article/10.1007/s00018-005-5386-7
- Ito, R. et al. Cleavage of oxidized guanine nucleotide and ADP sugar by human NUDT5 protein. J Biochem 149, 731–738 (2011). https://academic.oup.com/jb/article-abstract/149/6/731/2182605
- Li, D.-N. et al. The high expression of MTH1 and NUDT5 promotes tumor metastasis and indicates a poor prognosis in patients with non-small-cell lung cancer. Biochim Biophys Acta Mol Cell Res 1868, 118895 (2021). https://www.sciencedirect.com/science/article/abs/pii/S0167488920302536
- Zhang, H. et al. The high expression of NUDT5 indicates poor prognosis of breast cancer by modulating AKT / Cyclin D signaling. PLOS ONE 16, e0245876 (2021). https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245876
- Pickup, K. E. et al. Expression of Oncogenic Drivers in 3D Cell Culture Depends on Nuclear ATP Synthesis by NUDT5. Cancers 11, 1337 (2019). https://www.mdpi.com/2072-6694/11/9/1337
- Page, B. D. G. et al. Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells. Nat Commun 9, 250 (2018). https://www.nature.com/articles/s41467-017-02293-7