NCAT · Nudix hydrolases in Cancer Therapy

Nudix hydrolases in Cancer Therapy

In this multidisciplinary project, I have established several national and international collaborations with the objective to: a) Determine synthetic sick/lethal interactions (SSLI) within the Nudix protein family b) Investigate the role of Nudix proteins in modulating survival to anti-cancer treatments and resistance c) Investigate the functional role of the 22 Nudix proteins in cancer d) Identify novel SSLI in order to design novel molecular anti-cancer therapies e) Develop novel molecular therapies, such as inhibitors targeting key members of the Nudix proteins that play a role in cancer development and resistance to current anti- cancer therapies f) Determine a Nudix-framework functional network in cancer in order to develop novel biomarkers for cancer as well as diagnostic tools for prognosis The nucleoside diphosphate linked to another moiety-X family (Nudix) hydrolases, are a group of enzymes involved in several biological processes such as nucleotide, purine base and phospholipid metabolism, as well as mRNA processing. There are 22 members in the Nudix family, substrates of which are partially known such as dNTPs, diadenosine polyphosphates, nucleotide sugars and capped mRNAs. In various cases the substrates are shared among the Nudix enzymes, but several have unique affinity for certain molecules. The Nudix enzymes are conserved throughout all species, however it is unclear what biological function some of these enzymes have, moreover, it is unknown if there is a functional redundancy among the family members. In order to elucidate if the Nudix enzymes are mutually dependent, I have used small interference RNA to knockdown all the Nudix members in a pairwise manner in several non transformed and cancer cell lines, thereby generating a matrix containing 276 combinations that results in a Nudix genetic interaction network. We have also profiled the catalytic activity of the majority of the Nudix members towards several known and unknown substrates. The results of this enzymatic activity profile corroborated previously known substrates, confirming that our approach was correct, but also, and importantly, provided novel insights into previously non-described activities. We have also identified one of the Nudix hydrolases to be highly up-regulated in Cisplatin resistant cancer cells, and we are developing an inhibitor against this Nudix hydrolase in order to sensitize these resistant cells to chemotherapeutics. Additionally, in collaboration with the Human Protein Atlas, we have collected expression levels, subcellular localization, and tissue expression for most of the Nudix family members. Taken altogether we have created a comprehensive Nudix enzymes profiling that will allow for a better understanding of the biological functionality of these enzymes and their possible implications in cancer. In the future we anticipate that information from this project can assist in the development of new cancer therapeutics and/or diagnostics for the benefit of cancer patients world-wide. This work will shortly become publicly available in the form of a published research resource paper in a peer-reviewed scientific journal. Additional results from the current project have been published in: - Palazzo, L., Thomas, B., Jemth, A.-S., Colby, T., Leidecker, O., Feijs, K. L. H., et al. (2015). Processing of protein ADP-ribosylation by Nudix hydrolases. Biocehmical Journal 468(2) 293-301) - Puigvert JC, Sanjiv K and Helleday T. Targeting DNA repair, DNA metabolism and replication stress as anti-cancer strategies. FEBS journal (State-of-the-art minireview) accepted for publication. Contact information: Marie Curie fellow: Jordi Carreras Puigvert, Karolinska Institutet, Science for Life Laboratory, Box 1031, 171 21 Stockholm, Sweden. Email: jordi.carreras.puigvert@scilifelab.se Scientist in charge: Professor Thomas Helleday: Karolinska Institutet, Science for Life Laboratory, Box 1031, 171 21 Stockholm, Sweden. Email: thomas.helleday@scilifelab.se

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