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 language | English (US) |
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Pages (from-to) | 7603-7611 |
Number of pages | 9 |
Journal | Cancer research |
Volume | 69 |
Issue number | 19 |
DOIs | |
State | Published - Oct 1 2009 |
ASJC Scopus subject areas
- Oncology
- Cancer Research