Atypical protein kinase C{iota} is required for bronchioalveolar stem cell expansion and lung tumorigenesis.

Abstract

Protein kinase Ciota (PKCiota) is an oncogene required for maintenance of the transformed phenotype of non-small cell lung cancer cells. However, the role of PKCiota 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 PKCiota 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 PKCiota 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 PKCiota as a therapeutic target and for the clinical use of aurothiomalate for lung cancer treatment.

• Authors: Roderick P Regala, Rebecca K Davis, Alyssa Kunz, Andras Khoor, Michael Leitges, Alan P Fields
• Journal: Cancer research (Cancer Res) Vol. 69 Issue 19 Pg. 7603-11 (Oct 01 2009) ISSN: 1538-7445 [Electronic] United States
• PMID: 19738040 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Isoenzymes
• Gold Sodium Thiomalate
• Protein Kinase C
• protein kinase C lambda

Topics

• Animals
• Bronchioles (enzymology, pathology)
• Carcinoma, Non-Small-Cell Lung (enzymology, genetics, pathology)
• Cell Transformation, Neoplastic (drug effects, genetics, metabolism, pathology)
• Genes, ras (drug effects)
• Gold Sodium Thiomalate (pharmacology)
• Humans
• Isoenzymes (deficiency, genetics, metabolism)
• Lung Neoplasms (enzymology, genetics, pathology)
• Male
• Mice
• Mice, Transgenic
• Protein Kinase C (deficiency, genetics, metabolism)
• Pulmonary Alveoli (enzymology, pathology)
• Stem Cells (enzymology, pathology)