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Ribonucleotide reductase M 2 is a promising molecular target for the treatment of oral squamous cell carcinoma

In our previous study, ribonucleotide reductase M2 (RRM2) was identified as a cancer-related gene commonly overexpressed in human oral squamous cell carcinoma (OSCC) cell lines. Herein, we attempted to determine whether targeting RRM2 may be a plausible therapeutic approach for the treatment of patients with OSCC. First, we examined the expression levels of RRM2 in human OSCC cell lines and tissues. Overexpression of RRM2 in OSCC was confirmed by western blot analysis. Subsequently, we investigated the effects of a synthetic small interfering RNA specific for RRM2 and gemcitabine (GEM), an inhibitor of RRM2 enzymatic activity, on the growth of human OSCC cell lines and primary cultured cells. Targeting RRM2 by RNA interference almost completely suppressed the expression of RRM2 and markedly suppressed the growth of both types of cells by >54.8%. GEM also reduced the growth rate of these cells by >83.0%. Finally, we evaluated the antitumor effects of GEM, cisplatin (CDDP), 5-fluorouracil (5-FU), and docetaxel (DOC) against OSCC cells using the collagen gel droplet embedded culture drug sensitivity test. OSCC cells were more sensitive to GEM and DOC than to CDDP and 5-FU, regardless of the expression level of RRM2 mRNA. These results suggested that RRM2 supported the growth of human OSCC cells and that targeting of RRM2, e.g., via GEM treatment, may be a promising therapeutic strategy for OSCC. Introduction More than 500,000 new cases of head and neck squamous cell carcinoma (HNSCC) occurred in 2008 worldwide. Oral squamous cell carcinoma (OSCC) is the most frequently occurring cancer among HNSCCs and is associated with a mortality rate of approximately 50%, as reported in 2008 (1). Despite the increasing knowledge of OSCC pathogenesis, as well as advances in chemotherapy, radiotherapy, and surgery, little improvement in the relative survival rate has been observed in OSCC during the past several decades (2). Therefore, a greater understanding of the pathogenesis of OSCC is needed for the development of optimal therapeutic approaches. Cancer cells acquire abnormalities in multiple oncogenes and tumor-suppressor genes. Overexpression and constitutive activation of some oncogenes support the proliferation, invasion, and metastasis of cancer cells. Inactivation of a single critical oncogene can induce cancer cells to differentiate into cells with a normal phenotype or to undergo apoptosis. This dependence on oncogenes for maintaining the cancer phenotype is an Achilles heel for cancer cells, which can be exploited in cancer therapy (3). In HNSCCs, including OSCC, the overexpression of epidermal growth factor receptor (EGFR) correlates with lymph node metastasis, risk of locoregional recurrence, and poor prognosis (4,5). Cetuximab, which targets EGFR, is used for patients with local advanced, recurrent, or metastatic HNSCC. Radiotherapy or platinum-based chemotherapy plus cetuximab improve locoregional control and overall survival (6,7). However, cetuximab is the only available molecular targeted drug for the treatment of OSCC. Thus, we previously attempted to identify useful target molecules for the treatment of OSCC using microarray analysis, and we identified 465 cancer-related genes that were commonly overexpressed in human OSCC cell lines (8). Among these genes, overexpression of ribonucleotide reductase M2 (RRM2), which is targeted by gemcitabine (GEM), has been shown to be involved in tumor progression in human malignancies (9). Ribonucleotide reductase (RR) catalyzes the conversion of ribonucleotide 5'-diphosphates to their 2'-deoxynucleotide form required for DNA synthesis. RRM2 is the catalytic subunit of RR and modulates its enzymatic activity (10-12). GEM binds to RRM2, replaces cytidine during DNA replication, and Ribonucleotide reductase M2 is a promising molecular target for the treatment of oral squamous cell carcinoma KAzUKI IwAMOTO, KOh-IChI NAKAshIRO, hIROshI TANAKA, NORIhIKO TOKUzEN and hIROYUKI hAMAKAwA Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, Toon, Ehime 791-0295, Japan Received December 2, 2014; Accepted January 30, 2015 DOI: 10.3892/ijo.2015.2912 Correspondence to: Dr Koh-Ichi Nakashiro, Department of Oral and Maxillofacial Surgery, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime 791-0295, Japan E-mail: nakako@m.ehime-u.ac.jp Abbreviations: CD-DST, collagen gel droplet embedded culture drug sensitivity test; GEM, gemcitabine; HNSCC, head and neck squamous cell carcinoma; OSCC, oral squamous cell carcinoma; RRM2, ribonucleotide reductase M2; siRRM2, small interfering RNA specific for RRM2