Protein kinase Cι is required for pancreatic cancer cell transformed growth and tumorigenesis

Michele L. Scotti, William R. Bamlet, Thomas Christopher Smyrk, Alan P Fields, Nicole R Murray

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Pancreatic cancer is the fourth leading cause of cancer deaths in the United States, with an overall 5-year survival rate of <5%. Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is highly resistant to conventional chemotherapies, underscoring the critical need for new molecular targets for pancreatic cancer chemotherapy. The KRAS proto-oncogene is mutated in >90% of PDAC. Protein kinase Cι (PKCι) is required for the oncogenic Ras-mediated transformed growth of lung cancer and intestinal epithelial cells. However, little is known about the role of PKCι in pancreatic cancer. In this study, we evaluated the expression of PKCι in human pancreatic cancer and the requirement for PKCι for the transformed growth and tumorigenicity of PDAC cells. We find that PKCι is significantly overexpressed in human pancreatic cancer, and high PKCι expression correlates with poor patient survival. Inhibition of PKCι expression blocks PDAC cell transformed growth in vitro and tumorigenicity in vivo. Inhibition of PKCι expression in pancreatic tumors also significantly reduces tumor angiogenesis and metastasis. Analysis of downstream PKCé effectors implicates the Rac1-MEK/ERK1/2 signaling axis in PKCι-mediated transformed growth and cellular invasion. Taken together, our data show a required role for PKCι in the transformed growth of pancreatic cancer cells and reveal a novel role for PKCι in pancreatic cancer cell metastasis and angiogenesis in vivo. Our results strongly indicate that PKCι will be an effective target for pancreatic cancer therapy.

Original languageEnglish (US)
Pages (from-to)2064-2074
Number of pages11
JournalCancer Research
Volume70
Issue number5
DOIs
StatePublished - Mar 1 2010

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Pancreatic Neoplasms
Protein Kinase C
Carcinogenesis
Growth
Neoplasm Metastasis
Neoplasms
Mitogen-Activated Protein Kinase Kinases
Cause of Death
Lung Neoplasms
Survival Rate
Epithelial Cells

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Protein kinase Cι is required for pancreatic cancer cell transformed growth and tumorigenesis. / Scotti, Michele L.; Bamlet, William R.; Smyrk, Thomas Christopher; Fields, Alan P; Murray, Nicole R.

In: Cancer Research, Vol. 70, No. 5, 01.03.2010, p. 2064-2074.

Research output: Contribution to journalArticle

Scotti, Michele L. ; Bamlet, William R. ; Smyrk, Thomas Christopher ; Fields, Alan P ; Murray, Nicole R. / Protein kinase Cι is required for pancreatic cancer cell transformed growth and tumorigenesis. In: Cancer Research. 2010 ; Vol. 70, No. 5. pp. 2064-2074.
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abstract = "Pancreatic cancer is the fourth leading cause of cancer deaths in the United States, with an overall 5-year survival rate of <5{\%}. Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is highly resistant to conventional chemotherapies, underscoring the critical need for new molecular targets for pancreatic cancer chemotherapy. The KRAS proto-oncogene is mutated in >90{\%} of PDAC. Protein kinase Cι (PKCι) is required for the oncogenic Ras-mediated transformed growth of lung cancer and intestinal epithelial cells. However, little is known about the role of PKCι in pancreatic cancer. In this study, we evaluated the expression of PKCι in human pancreatic cancer and the requirement for PKCι for the transformed growth and tumorigenicity of PDAC cells. We find that PKCι is significantly overexpressed in human pancreatic cancer, and high PKCι expression correlates with poor patient survival. Inhibition of PKCι expression blocks PDAC cell transformed growth in vitro and tumorigenicity in vivo. Inhibition of PKCι expression in pancreatic tumors also significantly reduces tumor angiogenesis and metastasis. Analysis of downstream PKC{\'e} effectors implicates the Rac1-MEK/ERK1/2 signaling axis in PKCι-mediated transformed growth and cellular invasion. Taken together, our data show a required role for PKCι in the transformed growth of pancreatic cancer cells and reveal a novel role for PKCι in pancreatic cancer cell metastasis and angiogenesis in vivo. Our results strongly indicate that PKCι will be an effective target for pancreatic cancer therapy.",
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