PMID- 21242979
OWN - NLM
STAT- MEDLINE
DCOM- 20110616
LR  - 20211020
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 30
IP  - 15
DP  - 2011 Apr 14
TI  - Akt1 deletion prevents lung tumorigenesis by mutant K-ras.
PG  - 1812-21
LID - 10.1038/onc.2010.556 [doi]
AB  - K-ras mutations are associated with smoking-induced lung cancer and poor clinical 
      outcomes. In mice, K-ras mutations are sufficient to induce lung tumors, which 
      require phosphoinoside-3-kinase (PI3K) and further downstream, mammalian target 
      of rapamycin (mTOR) activation. However, the roles of individual Akt isoforms 
      that link PI3K and mTOR are unknown. Here, we show that deletion of Akt1 but not 
      Akt2 or Akt3 prevents lung tumorigenesis in a tobacco carcinogen-induced model 
      and a genetic model. Akt1 deletion prevented tumor initiation as well as tumor 
      progression, coincident with decreased Akt signaling in tumor tissues. In 
      contrast, deletion of Akt3 increased tumor multiplicity in the carcinogen model 
      and increased tumor size in the genetic model. Fibroblasts lacking Akt1 are 
      resistant to transformation by mutant K-ras and stimulation by epidermal growth 
      factor. Human lung cancer cells with mutant K-ras and diminished Akt1 levels fail 
      to grow in vivo. These data suggest that Akt1 is the primary Akt isoform 
      activated by mutant K-ras in lung tumors, and that Akt3 may oppose Akt1 in lung 
      tumorigenesis and lung tumor progression. Given that Akt inhibitors in clinical 
      development as cancer therapeutics are not isoform selective, these studies 
      support specific targeting of Akt1 to mitigate the effects of mutant K-ras in 
      lung cancer.
FAU - Hollander, M C
AU  - Hollander MC
AD  - Medical Oncology Branch, NCI, NIH, Bethesda, MD 20889, USA.
FAU - Maier, C R
AU  - Maier CR
FAU - Hobbs, E A
AU  - Hobbs EA
FAU - Ashmore, A R
AU  - Ashmore AR
FAU - Linnoila, R I
AU  - Linnoila RI
FAU - Dennis, P A
AU  - Dennis PA
LA  - eng
GR  - P30 CA006973/CA/NCI NIH HHS/United States
GR  - ImNIH/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
DEP - 20110117
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - EC 2.7.11.1 (Akt1 protein, mouse)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Animals
MH  - *Gene Deletion
MH  - *Genes, ras
MH  - Lung Neoplasms/genetics/*prevention & control
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Proto-Oncogene Proteins c-akt/genetics/*physiology
PMC - PMC4133779
MID - NIHMS608165
COIS- Conflict of interest The authors declare no conflict of interest.
EDAT- 2011/01/19 06:00
MHDA- 2011/06/17 06:00
PMCR- 2014/08/15
CRDT- 2011/01/19 06:00
PHST- 2011/01/19 06:00 [entrez]
PHST- 2011/01/19 06:00 [pubmed]
PHST- 2011/06/17 06:00 [medline]
PHST- 2014/08/15 00:00 [pmc-release]
AID - onc2010556 [pii]
AID - 10.1038/onc.2010.556 [doi]
PST - ppublish
SO  - Oncogene. 2011 Apr 14;30(15):1812-21. doi: 10.1038/onc.2010.556. Epub 2011 Jan 
      17.