Protein Kinase C Zeta Regulates Human Pancreatic Cancer Cell Transformed Growth and Invasion through a STAT3-Dependent Mechanism

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.

Protein Kinase C (PKC) Isozymes and Cancer

“…PKC participates in survival and metastasis of pancreatic cancer cells through the Stat3-dependent pathway [405][406][407] and Sp1-dependent VPE/VEGF expression, which is associated with cancer angiogenesis [408].…”

Targeting protein kinase C subtypes in pancreatic cancer

“…PKCζ expression and localization is similar in normal pancreas, pancreatic ductal adenocarcinoma cells and carcinoma tissue [33]. In pancreatic cancers PKCζ is required for transformed growth and invasion and this is mediated by PKCζ-induced activation of STAT3 [34]. Similar to PKCζ, PKCι also is required for pancreatic cancer cell transformed growth and tumorigenesis, but acts through the Rac1-MAPK pathway [30].…”

C1q/TNF‐related peptide 8 (CTRP8) promotes temozolomide resistance in human glioblastoma

“…CTRP8‐RXFP1 is emerging as a new ligand–receptor system which promotes GBM migration (Glogowska et al ., 2013) and, as shown here, protects against the cytotoxic effects of the DNA alkylating drug TMZ. Likely initiated by an interaction of RXFP1 with the small G protein Gα i3 to activate the Gα i3 ‐Gβγ‐PI3K signaling pathway (Nguyen and Dessauer, 2005), our discovery of a novel CTRP8‐RXFP1‐STAT3 signaling cascade in human GBM links this CTRP8‐RXFP1 system to oncogenic STAT3 functional outcomes, including GBM cell survival, angiogenesis, and cell migration/invasion (Aziz et al ., 2010; Butler et al ., 2013; Ouedraogo et al ., 2017). CTRP8‐activated RXFP1 may utilize PI3K to mediate STAT3 activation as PI3K and its target BMX TEC kinase were recently shown to mediate the phosphorylation of STAT3 (Glogowska et al ., 2013; Hart et al ., 2011).…”