KRAS-mediated Up-regulation of RRM2 Expression Is Essential for the Proliferation of Colorectal Cancer Cell Lines

Background: We previously investigated the mRNA expression of colorectal cancer cell lines via a microarray analysis and found several genes that were significantly up- regulated by oncogenic KRAS under serum-starved conditions. Of these genes, we focused on ribonucleotide reductase M2 (RRM2), which was reported to be associated with DNA synthesis. Materials and Methods: Cell proliferation and colony formation assays were performed using HCT116 cells transfected with lentiviral RRM2-shRNAs. Results: Under serum-starved conditions, the expression level of RRM2 protein increased in HCT116 cells compared to HKe3 cells (HCT116 cells with a disruption in oncogenic KRAS), and the re-expression of KRAS in HKe3 cells induced the expression of RRM2. Both the cell proliferation under serum-depleted conditions and the anchorage-independent growth were impaired by the reduction of RRM2 protein expression. Conclusion: RRM2 represents a novel therapeutic target, thus highlighting the potential utility of RRM2 inhibitors in colorectal cancer with oncogenic KRAS. KRAS mutations are frequently observed in colorectal cancer (CRC) and the precise oncogenic mechanism of KRAS in vivo has been intensively studied; however, KRAS-targeted therapy has not been clinically developed, and patients with CRC bearing oncogenic KRAS do not benefit from cetuximab, a monoclonal antibody against the epidermal growth factor receptor. We previously established HKe3 cells, human CRC HCT116 cells disrupted at oncogenic KRAS (1),