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FP7

NCAT Result In Brief

Project ID: 332428
Funded under: FP7-PEOPLE
Country: Sweden

Cancer and reactive oxygen species

Cancer is associated with genomic instability, which is often triggered by DNA lesions caused by reactive oxygen species (ROS). A European project investigated the protein family linked to ROS generation in cancer cells.
Cancer and reactive oxygen species
The protein family of hydrolase enzymes called NUDIX (nucleoside diphosphate linked to another moiety-X) contains 22 members, which are conserved throughout all species. These enzymes are involved in metabolism of nucleotides, purine bases and phospholipids in addition to mRNA processing.

NUDIX substrates are dNTPs, diadenosine polyphosphates, nucleotide sugars and capped mRNAs. The biological function of many of these enzymes is still unknown. The EU-funded NCAT (NUDIX hydrolases in cancer therapy) project studied the biological and biochemical roles of all the NUDIX hydrolases and their involvement in triggering tumorigenesis.

NUDIX enzymes oxidise lesions such as 8-oxodGTP present in the nucleotide pool, preventing their incorporation into the RNA or the DNA. Cancer cells show abnormally high levels of ROS generated by deregulated metabolism. Earlier data suggested that the NUDIX hydrolase MutT homologue 1 (MTH1) is overexpressed in cancer and that cancer cells require its activity for survival.

Researchers used small interference RNA technology to knockdown all the NUDIX members in a pairwise manner in several normal and cancer cell lines, thereby generating a matrix NUDIX genetic interaction network. They also determined expression levels, subcellular localisation, and tissue expression for most of the NUDIX proteins.

The majority of the NUDIX have similar structure and some share common substrates, which indicates redundancy of functions. Scientist also found variations of NUDIX expressions depending on the tissue, the cancer type and the cell line. Several NUDIX enzymes might be involved in cell cycle regulation.

Importantly, one of the NUDIX hydrolases was found to be up-regulated in Cisplatin resistant cancer cells. Thus, researchers initiated the development of an inhibitor against this hydrolase to sensitise the resistant cells to chemotherapeutics.

The NCAT project comprehensively profiled NUDIX enzymes allowing a better understanding of their biological functions. This should help elucidate the possible implications of hydrolases in tumorigenesis and refractory cancer. Applications include personalised cancer therapy.

Related information

Keywords

Cancer, reactive oxygen species, hydrolase, NUDIX, NCAT, small interference RNA technology
Record Number: 183118 / Last updated on: 2016-08-02
Domain: Biology, Medicine