Protein Kinase Cι Is Required for Pancreatic Cancer Cell Transformed Growth and Tumorigenesis

Pancreatic cancer is the fourth leading cause of cancer deaths in the United States, with an overall 5-year survival rate of <5%. Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is highly resistant to conventional chemotherapies, underscoring the critical need for new molecular targets for pancreatic cancer chemotherapy. The KRAS proto-oncogene is mutated in >90% of PDAC. Protein kinase C iota (PKC iota) is required for the oncogenic Ras-mediated transformed growth of lung cancer and intestinal epithelial cells. However, little is known about the role of PKC iota in pancreatic cancer. In this study, we evaluated the expression of PKC iota in human pancreatic cancer and the requirement for PKC iota for the transformed growth and tumorigenicity of PDAC cells. We find that PKC iota is significantly overexpressed in human pancreatic cancer, and high PKC iota expression correlates with poor patient survival. Inhibition of PKC iota expression blocks PDAC cell transformed growth in vitro and tumorigenicity in vivo. Inhibition of PKC iota expression in pancreatic tumors also significantly reduces tumor angiogenesis and metastasis. Analysis of downstream PKC iota effectors implicates the Rac1-MEK/ERK1/2 signaling axis in PKC iota-mediated transformed growth and cellular invasion. Taken together, our data show a required role for PKC iota in the transformed growth of pancreatic cancer cells and reveal a novel role for PKC iota in pancreatic cancer cell metastasis and angiogenesis in vivo. Our results strongly indicate that PKC iota will be an effective target for pancreatic cancer therapy. Cancer Res; 70(5); 2064-74. (C)2010 AACR.