Aberrant activation of Ras or Raf in mitogen-activated protein kinase (MAPK) signaling has been linked with cancer. Although constitutively activated MEK1, which doesn’t exit in nature, is “oncogenic”, the role of MAPK kinase (MAPKK or MEK) in cancer is unclear. Herein, we found that T-cell-originated protein kinase (TOPK), a member of the MEK protein family, is highly expressed in human colorectal cancer tissues and cell lines. We studied the biological consequences of overexpression or knockdown of TOPK in JB6 Cl41 and HCT116 colorectal cancer cells, respectively. TOPK was shown to promote abnormal proliferation in vitro and in vivo and knockdown of TOPK in HCT116 colorectal cancer cells reduced this cell line’s tumorigenic properties. Furthermore, a positive feedback loop between TOPK and ERK2 was identified in vitro and in vivo. With epidermal growth factor (EGF) treatment, knockdown of either TOPK or ERK2 in HCT116 cells resulted in decreased phosphorylation of ERK2 or TOPK, respectively, and knockdown of TOPK in HCT116 colorectal cancer cells blocked the phosphorylation of downstream substrates of ERK2. Thus we found that TOPK is the first oncogene discovered in the MEK family, which suggested that TOPK-regulated signaling may serve as a potential therapeutic target in colorectal cancer.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA