Prkci Regulates Autophagy and Pancreatic Tumorigenesis in Mice.

Kristin Inman,Murli Krishna,Michael Leitges,Nicole Murray,Yi Liu,Howard Crawford,Michele Scotti Buzhardt,Alan Fields

doi:10.3390/cancers14030796

Abstract

Simple SummaryPancreatic cancer is a highly fatal disease that does not respond well to current cancer therapies. We previously showed that protein kinase C iota (PKCι) is highly expressed in pancreatic cancer, and inhibition of PKCι signaling in human pancreatic cell lines blocks tumor growth. In this study, we used a genetic mouse model to investigate the role of PKCι in pancreatic cellular homeostasis and pancreatic tumorigenesis. We found that inhibition of PKCι expression in the mouse pancreas blocked autophagy, altered infiltration of immune cells, and prevented pancreatic cancer formation. Taken together, these findings reveal a promotive role for PKCι in pancreatic cancer development.Protein kinase C iota (PKCι) functions as a bonafide human oncogene in lung and ovarian cancer and is required for KrasG12D-mediated lung cancer initiation and progression. PKCι expression is required for pancreatic cancer cell growth and maintenance of the transformed phenotype; however, nothing is known about the role of PKCι in pancreas development or pancreatic tumorigenesis. In this study, we investigated the effect of pancreas-specific ablation of PKCι expression on pancreatic cellular homeostasis, susceptibility to pancreatitis, and KrasG12D-mediated pancreatic cancer development. Knockout of pancreatic Prkci significantly increased pancreatic immune cell infiltration, acinar cell DNA damage, and apoptosis, but reduced sensitivity to caerulein-induced pancreatitis. Prkci-ablated pancreatic acinar cells exhibited P62 aggregation and a loss of autophagic vesicles. Loss of pancreatic Prkci promoted KrasG12D-mediated pancreatic intraepithelial neoplasia formation but blocked progression to adenocarcinoma, consistent with disruption of autophagy. Our results reveal a novel promotive role for PKCι in pancreatic epithelial cell autophagy and pancreatic cancer progression.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer
We and others have shown that PKCι expression is significantly elevated in oncogenic KrasG12D-transformed, metaplastic pancreatic acinar cells, suggesting that PKCι plays a significant role in the initiation of pancreatic cancer [22,47]
We report that ablation of PKCι expression in the mouse pancreas altered the pancreatic immune cell population, reduced the severity of caeruleininduced pancreatitis, and blocked KrasG12D-driven progression of PanINs to pancreatic cancer, revealing for the first time a role for PKCι in the promotion of PDAC in mice

Summary

Introduction

With a 5-year survival rate of 10%, PDAC is predicted to result in over 48,000 deaths in the U.S in 2021 [1] This high mortality rate is attributable to late detection and poor response of PDAC to conventional therapies. PanIN lesion initiation and progression continue over the lifespan of the mouse with a small subset of the high grade PanINs progressing to pancreatic cancer [8]. The overall similarity of this model to human disease development makes the KC mouse a useful GEMM to assess the role of specific genes in pancreatic tumorigenesis and to evaluate potential therapeutic targets for the prevention and treatment of PDAC [9,10,11]

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