PMID- 23604119
OWN - NLM
STAT- MEDLINE
DCOM- 20140623
LR  - 20211021
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 33
IP  - 16
DP  - 2014 Apr 17
TI  - Protein kinase Calpha suppresses Kras-mediated lung tumor formation through 
      activation of a p38 MAPK-TGFbeta signaling axis.
PG  - 2134-44
LID - 10.1038/onc.2013.147 [doi]
AB  - Protein kinase C alpha (PKCalpha) can activate both pro- and anti-tumorigenic 
      signaling depending upon cellular context. Here, we investigated the role of PKCalpha 
      in lung tumorigenesis in vivo. Gene expression data sets revealed that primary 
      human non-small lung cancers (NSCLC) express significantly decreased PKCalpha levels, 
      indicating that loss of PKCalpha expression is a recurrent event in NSCLC. We 
      evaluated the functional relevance of PKCalpha loss during lung tumorigenesis in 
      three murine lung adenocarcinoma models (LSL-Kras, LA2-Kras and urethane 
      exposure). Genetic deletion of PKCalpha 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 PKCalpha 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 TGFbeta1 mRNA, and addition of exogenous TGFbeta1 to LSL-Kras BASCs results in 
      enhanced growth similar to untreated BASCs from LSL-Kras/Prkca(-/-) mice. 
      Conversely, a TGFbetaR1 inhibitor reversed the effects of PKCalpha 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 
      PKCalpha-dependent tumor suppressor activity in vitro and in vivo. We conclude that 
      PKCalpha suppresses tumor initiation and progression, at least in part, through a 
      PKCalpha-p38MAPK-TGFbeta signaling axis that regulates tumor cell proliferation and 
      Kras-induced senescence. Our results provide the first direct evidence that PKCalpha 
      exhibits tumor suppressor activity in the lung in vivo.
FAU - Hill, K S
AU  - Hill KS
AD  - Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
FAU - Erdogan, E
AU  - Erdogan E
AD  - Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
FAU - Khoor, A
AU  - Khoor A
AD  - Department of Pathology, Mayo Clinic, Jacksonville, FL, USA.
FAU - Walsh, M P
AU  - Walsh MP
AD  - Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
FAU - Leitges, M
AU  - Leitges M
AD  - The Oslo Biotechnology Centre, Oslo, Norway.
FAU - Murray, N R
AU  - Murray NR
AD  - Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
FAU - Fields, A P
AU  - Fields AP
AD  - Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
LA  - eng
GR  - R01 CA140290/CA/NCI NIH HHS/United States
GR  - R01 CA081436/CA/NCI NIH HHS/United States
GR  - R01 CA140290-03/CA/NCI NIH HHS/United States
GR  - P30 CA015083/CA/NCI NIH HHS/United States
GR  - R01 CA081436-16/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20130422
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Inhibitor of Differentiation Proteins)
RN  - 0 (Transforming Growth Factor beta)
RN  - 0 (WT1 Proteins)
RN  - EC 2.7.11.13 (Protein Kinase C-alpha)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 3.6.5.2 (Hras protein, mouse)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
SB  - IM
MH  - Animals
MH  - Bronchioles/metabolism/pathology
MH  - Cells, Cultured
MH  - Disease Models, Animal
MH  - Enzyme Activation
MH  - Female
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Immunohistochemistry
MH  - Inhibitor of Differentiation Proteins/genetics/metabolism
MH  - Lung Neoplasms/*genetics/metabolism/pathology
MH  - Male
MH  - Mice
MH  - Mice, 129 Strain
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Protein Kinase C-alpha/*genetics/metabolism
MH  - Proto-Oncogene Proteins p21(ras)/*genetics/metabolism
MH  - Pulmonary Alveoli/metabolism/pathology
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction/*genetics
MH  - Stem Cells/metabolism/pathology
MH  - Transforming Growth Factor beta/*genetics/metabolism
MH  - WT1 Proteins/genetics/metabolism
MH  - p38 Mitogen-Activated Protein Kinases/*genetics/metabolism
PMC - PMC3895109
MID - NIHMS543393
COIS- CONFLICT OF INTEREST The authors declare no conflict of interest.
EDAT- 2013/04/23 06:00
MHDA- 2014/06/24 06:00
PMCR- 2014/04/18
CRDT- 2013/04/23 06:00
PHST- 2012/12/13 00:00 [received]
PHST- 2013/03/08 00:00 [revised]
PHST- 2013/03/11 00:00 [accepted]
PHST- 2013/04/23 06:00 [entrez]
PHST- 2013/04/23 06:00 [pubmed]
PHST- 2014/06/24 06:00 [medline]
PHST- 2014/04/18 00:00 [pmc-release]
AID - onc2013147 [pii]
AID - 10.1038/onc.2013.147 [doi]
PST - ppublish
SO  - Oncogene. 2014 Apr 17;33(16):2134-44. doi: 10.1038/onc.2013.147. Epub 2013 Apr 
      22.