RRM1 AFFECTS EXTRACELLULAR MATRIX REMODELING.

Ribonucleotide reductase large subunit M1 (RRM1), a rate-limiting enzyme in the DNA synthesis pathway, requires the conversion of ribonucleotides to dNTPs.(16) RRM1 has an effect on the poor disease prognosis of several cancers, including pancreatic cancer.(17-19) Furthermore, RRM1 has been associated with resistance to gemcitabine, an important drug in the treatment of pancreatic cancer.(19-21) However, the way in which RRM1 is involved in the biology of pancreatic cancer, especially related to cell motility, is poorly understood. In this study we investigated the relationship between epithelial-mesenchymal transition (EMT), motility invasion capacity, histone acetylation, and drug resistance in gemcitabine-resistant cell lines. We also performed in vitro overexpression or siRNA experiments to examine the functions of RRM1, concentrating on the relationship between invasiveness and changes in the expression of factors such as N-cadherin. We found that RRM1 contributed to the malignant phenotype of cancer cells, including increased motility and invasiveness, especially during gemcitabine resistance. Therefore, RRM1 might be a therapeutic target for the treatment of pancreatic cancer.