Abstract 1571: Nek2 as an effective molecular target for cancer treatment

Abstract

Abstract Nek2 (NIMA-related kinase 2) is a member of the serine/threonine kinase family, Nek, structurally related to the essential mitotic regulator NIMA. Nek2 is involved in cell division and mitotic regulation by centrosome splitting. Increased expression of Nek2 has been reported in cell lines derived from cervical and prostate cancer as well as lymphomas. We, therefore, examined the expression levels of Nek2 in various cancer cell lines, such as cholangiocarcinoma (HuCCT1, TFK1, HuH28, CCKS1, ETK1, RBE, IHGGK), breast cancer (BT20, BT474, Hs578T, MCF7, MDA-MB-231, T47D, ZR-75-1) and colorectal cancer (HCT-15, DLD-1, Colo205, Colo320). These cancer cells expressed higher levels of Nek2 mRNA and protein than those of HFF, a cell line derived from normal human fibroblast. The expression of Nek2 was also elevated in breast cancer and colorectal cancer tissue in compared with that of normal tissue. The Nek2 suppression with siRNA resulted in the inhibition of cell proliferation and induced cell death in these cancer cell lines. We next examined the effect of Nek2 siRNA treatment on the growth of cholangiocarcinoma tumor in xenograft-nude mouse model. Mean tumor volumes in Nek2 siRNA-treated mice were substantially reduced in comparison with those of the control mice. The Nek2 expression in the tumor tissues was dramatically suppressed in Nek2 siRNA treated tumors, as compared with those of control siRNA treated tumors. Nek2 siRNA also resulted in reduction of tumor size as compared with those of control siRNA injection in breast cancer tumor and colorectal cancer tumor. To further evaluate the effects of Nek2 siRNA treatment, we challenged siRNA in the peritoneal dissemination model. It should be noted that peritoneal dissemination is one of the major undesirable complications frequently associated with inoperable cases. In peritoneal dissemination model, Nek2 siRNA-treated mice showed statistically longer survival periods in comparison with those of the control siRNA-treated mice. Survival rates of the Nek2 siRNA-treated mice were approximately 1.5 times higher than those of the control siRNA-treated mice. Taken together, for the improvement of cancer therapy, identification of specific molecular targets critical for its tumorigenicity is an important issue. Nek2 plays a critical role in tumorigenic growth of various cancers, and inhibition of Nek2 expression with its siRNA causes suppression of cancer growth and survival. Our data in vivo provides a strong rationale for the further investigation of Nek2 inhibitors as a new cancer therapy, holding the potential to provide regression of multiple human malignancies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1571.