Protein Kinase C Zeta Regulates Human Pancreatic Cancer Cell Transformed Growth and Invasion through a STAT3-Dependent Mechanism
Year: 2013
Type: article
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.
Source: PLoS ONE
Authors: Amanda M. Butler, Michele L. Scotti Buzhardt, Shuhua Li, Kristin E. Smith, Alan P. Fields, Nicole R. Murray
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,382
Awards: Protein Kinase C Signaling Mechanisms in Cancer, G1655353241, G2075094911, Role of atypical PKCs in Pancreatic Tumor Growth and Metastasis, PKCz; a novel therapeutic target for pancreatic cancer 'stem cells', G3015188539, Mayo Clinic SPORE in Pancreatic Cancer, G6667116099, G6912916513, Role of PKC iota in metaplasia and initiation of pancreatic cancer, G815598048, G9000146046
OpenAlex ID: W2094810540