Angiotensin II type 2 receptor gene deficiency attenuates susceptibility to tobacco-specific nitrosamine-induced lung tumorigenesis: involvement of transforming growth factor-beta-dependent cell growth attenuation.
To clarify an involvement of angiotensin II signaling in lung neoplasia, we have examined the effect of angiotensin II receptor deficiency on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis. Male angiotensin II type 2 receptor (AT2)-null mice with an SWR/J genetic background and control wild-type mice were treated with NNK (100 mg/kg, i.p.) or saline vehicle. NNK treatment caused the development of lung tumors in all wild-type control mice (100 % tumor prevalence), but only 85% of AT2-null mice developed tumors. The tumor multiplicity in AT2-null mice (1.9 +/- 0.3) was significantly smaller than that in wild-type mice (4.1 +/- 0.9). Primary cultured lung fibroblasts prepared from both AT2-null and wild-type mice markedly increased the colony counts of A549 lung cancer cells in soft agar, but a consistently higher colony count was observed with the wild-type fibroblasts (fold increase in colony number, 5.6 +/- 0.5) than with the AT2-null fibroblasts (3.5 +/- 0.8). The underlying mechanism by which angiotensin II regulates cancer cell growth is due to the regulation of active transforming growth factor-beta (TGF-beta) production. Although the total level of TGF-beta was significantly stimulated when A549 cells were cocultured with either type of fibroblasts, the level of active TGF-beta in the conditioned medium was consistently higher with AT2-null fibroblasts than with wild-type fibroblasts. These results imply that the AT2 receptor negatively regulates the level of active TGF-beta and thus increases NNK-induced lung tumorigenesis. The AT2 receptor function in lung stromal fibroblasts may be a potential modulator of tumor susceptibility in chemical carcinogen-induced lung tumorigenesis.
Kanehira
Tsutomu
T
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Tani
Tatsuo
T
Takagi
Tetsuo
T
Nakano
Yuichirou
Y
Howard
Eric F
EF
Tamura
Masaaki
M
D057912:Angiotensin II Type 2 Receptor Blockers; D000818:Animals; D002273:Carcinogens; D048708:Cell Growth Processes / Q000502:physiology; D003043:Cocarcinogenesis; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics*; D008297:Male; D051379:Mice; D009602:Nitrosamines; D011506:Proteins / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists / Q000172:deficiency* / Q000235:genetics*
D057912:Angiotensin II Type 2 Receptor Blockers; D002273:Carcinogens; D009602:Nitrosamines; D011506:Proteins; D044139:Receptor, Angiotensin, Type 2; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone