Prkci Regulates Autophagy and Pancreatic Tumorigenesis in Mice

Kristin S. Inman; Yi Liu; Michele L. Scotti Buzhardt; Michael Leitges; Murli Krishna; Howard C. Crawford; Alan P. Fields; Nicole R. Murray

doi:10.3390/cancers14030796

Prkci Regulates Autophagy and Pancreatic Tumorigenesis in Mice

Kristin S. Inman, Yi Liu, Michele L. Scotti Buzhardt, Michael Leitges, Murli Krishna, Howard C. Crawford, Alan P. Fields, Nicole R. Murray

Research output: Contribution to journal › Article › peer-review

Abstract

Protein kinase C iota (PKCι) functions as a bonafide human oncogene in lung and ovarian cancer and is required for Kras^G12D-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 Kras^G12D-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 Kras^G12D-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.

Original language	English (US)
Article number	796
Journal	Cancers
Volume	14
Issue number	3
DOIs	https://doi.org/10.3390/cancers14030796
State	Published - Feb 1 2022

Keywords

Autophagy
Immune cell infiltration
Pancreatic cancer
Protein kinase C iota
Tumor progression

ASJC Scopus subject areas

Oncology
Cancer Research

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title = "Prkci Regulates Autophagy and Pancreatic Tumorigenesis in Mice",

abstract = "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.",

keywords = "Autophagy, Immune cell infiltration, Pancreatic cancer, Protein kinase C iota, Tumor progression",

author = "Inman, {Kristin S.} and Yi Liu and {Scotti Buzhardt}, {Michele L.} and Michael Leitges and Murli Krishna and Crawford, {Howard C.} and Fields, {Alan P.} and Murray, {Nicole R.}",

note = "Publisher Copyright: {\textcopyright} 2022 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2022",

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doi = "10.3390/cancers14030796",

language = "English (US)",

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AU - Inman, Kristin S.

AU - Liu, Yi

AU - Scotti Buzhardt, Michele L.

AU - Leitges, Michael

AU - Krishna, Murli

AU - Crawford, Howard C.

AU - Fields, Alan P.

AU - Murray, Nicole R.

PY - 2022/2/1

Y1 - 2022/2/1

N2 - 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.

AB - 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.

KW - Autophagy

KW - Immune cell infiltration

KW - Pancreatic cancer

KW - Protein kinase C iota

KW - Tumor progression

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Prkci Regulates Autophagy and Pancreatic Tumorigenesis in Mice

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Keywords

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