Atypical protein kinase C{iota} is required for bronchioalveolar stem cell expansion and lung tumorigenesis.
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.
Regala
Roderick P
RP
Departments of Cancer Biology and Pathology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida, USA.
Davis
Rebecca K
RK
Kunz
Alyssa
A
Khoor
Andras
A
Leitges
Michael
M
Fields
Alan P
AP
D000818:Animals; D055745:Bronchioles / Q000201:enzymology / Q000473:pathology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011905:Genes, ras / Q000187:drug effects; D006052:Gold Sodium Thiomalate / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011493:Protein Kinase C / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000201:enzymology / Q000473:pathology*; D013234:Stem Cells / Q000201:enzymology / Q000473:pathology*; D000099293:Protein Kinase C-lambda
D006052:Gold Sodium Thiomalate; D007527:Isoenzymes; D011493:Protein Kinase C; D000099293:Protein Kinase C-lambda