Atypical protein kinase Cι is required for bronchioalveolar stem cell expansion and lung tumorigenesis

Roderick P. Regala, Rebecca K. Davis, Alyssa Kunz, Andras Khoor, Michael Leitges, Alan P Fields

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Protein kinase Cι (PKCι) is an oncogene required for maintenance of the transformed phenotype of non-small cell lung cancer cells. However, the role of PKCι in lung tumor development has not been investigated. To address this question, we established a mouse model in which oncogenic Kras G12D is activated by Cre-mediated recombination in the lung with or without simultaneous genetic loss of the mouse PKCι gene, Prkci. Genetic loss of Prkci dramatically inhibits Kras-initiated hyperplasia and subsequent lung tumor formation in vivo. This effect correlates with a defect in the ability of Prkci-deficient bronchioalveolar stem cells to undergo Kras-mediated expansion and morphologic transformation in vitro and in vivo. Furthermore, the small molecule PKCι inhibitor aurothiomalate inhibits Kras-mediated bronchioalveolar stem cell expansion and lung tumor growth in vivo. Thus, Prkci is required for oncogene-induced expansion and transformation of tumor-initiating lung stem cells. Furthermore, aurothiomalate is an effective antitumor agent that targets the tumor-initiating stem cell niche in vivo. These data have important implications for PKCι as a therapeutic target and for the clinical use of aurothiomalate for lung cancer treatment.

Original languageEnglish (US)
Pages (from-to)7603-7611
Number of pages9
JournalCancer Research
Volume69
Issue number19
DOIs
StatePublished - Oct 1 2009

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Protein Kinase C
Gold Sodium Thiomalate
Carcinogenesis
Stem Cells
Lung
Neoplastic Stem Cells
Oncogenes
Neoplasms
Stem Cell Niche
Protein C Inhibitor
Protein Kinase Inhibitors
Non-Small Cell Lung Carcinoma
Antineoplastic Agents
Genetic Recombination
Hyperplasia
Lung Neoplasms
Maintenance
PKC-3 protein
Phenotype
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Atypical protein kinase Cι is required for bronchioalveolar stem cell expansion and lung tumorigenesis. / Regala, Roderick P.; Davis, Rebecca K.; Kunz, Alyssa; Khoor, Andras; Leitges, Michael; Fields, Alan P.

In: Cancer Research, Vol. 69, No. 19, 01.10.2009, p. 7603-7611.

Research output: Contribution to journalArticle

Regala, Roderick P. ; Davis, Rebecca K. ; Kunz, Alyssa ; Khoor, Andras ; Leitges, Michael ; Fields, Alan P. / Atypical protein kinase Cι is required for bronchioalveolar stem cell expansion and lung tumorigenesis. In: Cancer Research. 2009 ; Vol. 69, No. 19. pp. 7603-7611.
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