Abstract B63: Protein kinase C zeta plays an important role in the oncogenic phenotype of pancreatic cancer cells.

Abstract

Pancreatic cancer remains the fourth leading cause of cancer deaths in the United States due, in part, to its propensity for invasion and metastasis. Protein kinase C zeta (PKCζ) has been shown to regulate migration and invasion of both normal and malignant cell types. PKCζ has been shown to play a procarcinogenic role in various cancer types, including breast, colon, and glioblastoma; however, a role for PKCζ in the transformed growth of pancreatic cancer has not been demonstrated. We hypothesized that PKCζ may contribute to the lethality of pancreatic cancer by promoting cancer cell invasion and metastasis. Consistent with the hypothesis that PKCζ plays a role in the pancreatic cancer phenotype, PKCζ is overexpressed in a subset of human pancreatic tumors compared to associated non-tumor pancreas tissue. In the present study we use RNAi-mediated inhibition of PKCζ expression to investigate the role of PKCζ in the growth and invasion of pancreatic cancer cells. Inhibition of PKCζ reduces log phase growth and survival of human pancreatic cancer cell lines, with a corresponding reduction in colony formation in soft agar. Inhibition of PKCζ significantly reduces the size of tumors formed by human pancreatic cancer cells in a mouse orthotopic tumor model. Analysis of the isolated orthotopic tumors reveals a reduction in tumor cell proliferation in PKCζ RNAi tumors. In addition, PKCζ RNAi tumors exhibit elevated tumor necrosis compared to nontarget RNAi (control) tumors. Furthermore, PKCζ RNAi tumors produce fewer metastases to distal organs, corresponding to the reduced migration and invasion of PKCζ RNAi cells in vitro. Signal transducer and activator of transcription 3 (STAT3), which is often constitutively activated in pancreatic tumors and pancreatic cancer cell lines, has been implicated in pancreatic cancer cell survival and metastasis. Indeed, we observe reduced cell survival, migration and invasion in pancreatic cancer cells in which STAT3 signaling is inhibited. Interestingly, inhibition of PKCζ significantly reduces constitutive STAT3 phosphorylation in pancreatic cancer cells in vitro and in vivo. Taken together these data strongly support a required role for PKCζ in pancreatic cancer cell survival, migration and invasion, and indicate that STAT3 may be a downstream effector of PKCζ in pancreatic cancer. Citation Format: Amanda M. Butler, Michele L. Scotti, Shuhua Li, Alan P. Fields, Nicole R. Murray. Protein kinase C zeta plays an important role in the oncogenic phenotype of pancreatic cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr B63.