Akt1 deletion prevents lung tumorigenesis by mutant K-ras.
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.
Medical Oncology Branch, NCI, NIH, Bethesda, MD 20889, USA.
M C
MC
Hollander
C R
CR
Maier
E A
EA
Hobbs
A R
AR
Ashmore
R I
RI
Linnoila
P A
PA
Dennis
D000818:Animals; D017353:Gene Deletion; D011905:Genes, ras; D008175:Lung Neoplasms / Q000235:genetics / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000502:physiology*
C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
Expert Opin Ther Targets. 2008 Sep;12(9):1139-65
18694380
J Clin Oncol. 2006 Jan 10;24(2):306-14
16330671
Pigment Cell Melanoma Res. 2009 Aug;22(4):400-19
19493313
Curr Protoc Immunol. 2001 May;Chapter 10:Unit 10.17C
18432682
Cancer Res. 2007 Jan 1;67(1):167-77
17210696
Genes Dev. 2006 Jun 15;20(12):1569-74
16778075
Br J Biomed Sci. 2001;58(3):159-63
11575738
Nat Genet. 1999 Oct;23(2):176-84
10508513
Cancer Res. 2002 Jan 1;62(1):89-98
11782364
Cell Cycle. 2009 Aug 15;8(16):2502-8
19597332
Mol Cell Biol. 2002 Apr;22(7):2111-23
11884599
Mol Cell Biol. 2006 Nov;26(21):8042-51
16923958
Science. 2001 Jun 1;292(5522):1728-31
11387480
Br J Cancer. 2009 Jul 7;101(1):145-8
19491896
Clin Cancer Res. 2007 Apr 1;13(7):2281-9
17404113
Am J Respir Crit Care Med. 2008 Jul 1;178(1):60-73
18310482
Neoplasia. 2008 Aug;10(8):866-72
18683321
Int J Biol Markers. 2008 Jan-Mar;23(1):1-9
18409144
Cancer Res. 1989 Oct 1;49(19):5305-11
2670201
Mol Cell Biol. 2005 Mar;25(5):1869-78
15713641
Cell Cycle. 2008 Mar 1;7(5):665-9
18256540
Cancer Res. 2004 Jan 15;64(2):446-51
14744754
Toxicology. 1981;21(2):95-104
7281206
Biomaterials. 2009 Oct;30(29):5844-52
19640582
Exp Lung Res. 1998 Jul-Aug;24(4):481-97
9659579
Nature. 2001 Apr 26;410(6832):1111-6
11323676
Invest New Drugs. 2005 Oct;23(5):485-7
16133800
PLoS One. 2008 Mar 05;3(3):e0001722
18320023
Biochim Biophys Acta. 2005 Nov 25;1756(2):127-44
16139957
Cell. 2007 Jun 1;129(5):957-68
17540175
Cancer Metastasis Rev. 2005 Jun;24(2):273-85
15986137
Nature. 2006 May 25;441(7092):523-7
16680151
Cancer Cell. 2006 Oct;10(4):269-80
17045205
Cancer Cell. 2003 Aug;4(2):111-20
12957286
CA Cancer J Clin. 2010 Sep-Oct;60(5):277-300
20610543
Cancer Genet Cytogenet. 2009 May;191(1):34-7
19389506
Cancer Res. 2009 Jun 1;69(11):4885-93
19487299
Oncogene. 2010 Jan 7;29(1):150-5
19802009
Mol Cell Biol. 1996 Jul;16(7):3923-33
8668210
Cell. 2007 Jun 29;129(7):1261-74
17604717
Mol Cell Biol. 2003 Jun;23(11):3859-71
12748288
Mol Cell Biol. 2010 Feb;30(3):601-12
19933838
Proc Natl Acad Sci U S A. 2007 May 1;104(18):7438-43
17460049
Curr Oncol Rep. 2009 Mar;11(2):102-10
19216841
J Biol Chem. 2001 Oct 19;276(42):38349-52
11533044
Nature. 2007 Jul 26;448(7152):439-44
17611497
Br J Cancer. 2008 Oct 21;99(8):1265-8
18813315
Cell. 2008 Jun 27;133(7):1292-1292.e1
18585361
Int J Cancer. 2010 Jul 1;127(1):239-44
19876913