Abstract
Pancreatic cancer is a very aggressive disease with few therapeutic options. In this study, we investigate the role of protein kinase C zeta (PKCζ) in pancreatic cancer cells. PKCζ has been shown to act as either a tumor suppressor or tumor promoter depending upon the cellular context. We find that PKCζ expression is either maintained or elevated in primary human pancreatic tumors, but is never lost, consistent with PKCζ playing a promotive role in the pancreatic cancer phenotype. Genetic inhibition of PKCζ reduced adherent growth, cell survival and anchorage-independent growth of human pancreatic cancer cells in vitro. Furthermore, PKCζ inhibition reduced orthotopic tumor size in vivo by inhibiting tumor cell proliferation and increasing tumor necrosis. In addition, PKCζ inhibition reduced tumor metastases in vivo, and caused a corresponding reduction in pancreatic cancer cell invasion in vitro. Signal transducer and activator of transcription 3 (STAT3) is often constitutively active in pancreatic cancer, and plays an important role in pancreatic cancer cell survival and metastasis. Interestingly, inhibition of PKCζ significantly reduced constitutive STAT3 activation in pancreatic cancer cells in vitro and in vivo. Pharmacologic inhibition of STAT3 mimicked the phenotype of PKCζ inhibition, and expression of a constitutively active STAT3 construct rescued the transformed phenotype in PKCζ-deficient cells. We conclude that PKCζ is required for pancreatic cancer cell transformed growth and invasion in vitro and tumorigenesis in vivo, and that STAT3 is an important downstream mediator of the pro-carcinogenic effects of PKCζ in pancreatic cancer cells.
Highlights
Pancreatic cancer is the tenth most commonly diagnosed cancer in the U.S, and ranks fourth in lethality [1]
Functional studies have shown that the role of PKCf in regulating the cancer phenotype varies by tumor type, model system and stage of disease
Genetic inhibition of PKCf in a mouse model of KrasG12D-induced lung tumorigenesis reveals a tumor suppressor role [4], while inhibition of PKCf expression in lung cancer cells has no effect on transformed growth in vitro [20]
Summary
Pancreatic cancer is the tenth most commonly diagnosed cancer in the U.S, and ranks fourth in lethality [1]. PKC is known to be a family of related isoforms, and recent studies have characterized the specific roles of individual isoforms in susceptibility to, and development of, cancer [4,5,6,7,8,9,10]. We have demonstrated a pro-carcinogenic role for PKCi in pancreatic cancer cells [16]. Both tumor promotive and tumor suppressor roles have been attributed to PKCf [4,17,18], its role in pancreatic cancer has not been evaluated. We demonstrate that inhibition of PKCf in pancreatic cancer cells significantly impairs the cancer phenotype. Our data identify STAT3 as an important mediator of PKCf in the transformed growth and invasion of pancreatic cancer cells
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