title: Protein kinase Cα suppresses Kras-mediated lung tumor formation through activation of a p38 MAPK-TGFβ signaling axis.
abstract: Protein kinase C alpha (PKCα) can activate both pro- and anti-tumorigenic signaling depending upon cellular context. Here, we investigated the role of PKCα in lung tumorigenesis in vivo. Gene expression data sets revealed that primary human non-small lung cancers (NSCLC) express significantly decreased PKCα levels, indicating that loss of PKCα expression is a recurrent event in NSCLC. We evaluated the functional relevance of PKCα loss during lung tumorigenesis in three murine lung adenocarcinoma models (LSL-Kras, LA2-Kras and urethane exposure). Genetic deletion of PKCα resulted in a significant increase in lung tumor number, size, burden and grade, bypass of oncogene-induced senescence, progression from adenoma to carcinoma and a significant decrease in survival in vivo. The tumor promoting effect of PKCα loss was reflected in enhanced Kras-mediated expansion of bronchio-alveolar stem cells (BASCs), putative tumor-initiating cells, both in vitro and in vivo. LSL-Kras/Prkca(-/-) mice exhibited a decrease in phospho-p38 MAPK in BASCs in vitro and in tumors in vivo, and treatment of LSL-Kras BASCs with a p38 inhibitor resulted in increased colony size indistinguishable from that observed in LSL-Kras/Prkca(-/-) BASCs. In addition, LSL-Kras/Prkca(-/-) BASCs exhibited a modest but reproducible increase in TGFβ1 mRNA, and addition of exogenous TGFβ1 to LSL-Kras BASCs results in enhanced growth similar to untreated BASCs from LSL-Kras/Prkca(-/-) mice. Conversely, a TGFβR1 inhibitor reversed the effects of PKCα loss in LSL-Kras/Prkca(-/-) BASCs. Finally, we identified the inhibitors of DNA binding (Id) Id1-3 and the Wilm's Tumor 1 as potential downstream targets of PKCα-dependent tumor suppressor activity in vitro and in vivo. We conclude that PKCα suppresses tumor initiation and progression, at least in part, through a PKCα-p38MAPK-TGFβ signaling axis that regulates tumor cell proliferation and Kras-induced senescence. Our results provide the first direct evidence that PKCα exhibits tumor suppressor activity in the lung in vivo.
authors.affiliation: Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Hill
authors.affiliation: Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: E
authors.initials: E
authors.lastname: Erdogan
authors.affiliation: Department of Pathology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: A
authors.initials: A
authors.lastname: Khoor
authors.affiliation: Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Walsh
authors.affiliation: The Oslo Biotechnology Centre, Oslo, Norway.
authors.forename: M
authors.initials: M
authors.lastname: Leitges
authors.affiliation: Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: N R
authors.initials: NR
authors.lastname: Murray
authors.affiliation: Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: A P
authors.initials: AP
authors.lastname: Fields
mesh_terms: D000818:Animals; D055745:Bronchioles / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051571:Protein Kinase C-alpha / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D025721:WT1 Proteins / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D051796:Inhibitor of Differentiation Proteins; D016212:Transforming Growth Factor beta; D025721:WT1 Proteins; D051571:Protein Kinase C-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)