Hemizygous mice for the angiotensin II type 2 receptor gene have attenuated susceptibility to azoxymethane-induced colon tumorigenesis.
Evidence suggests that the use of angiotensin-converting enzyme inhibitors potentially reduces the risk of cancer, though the mechanism is unclear. To clarify a potential involvement of angiotensin II (Ang II) signaling in cancer risk, we have examined the effect of Ang II receptor deficiency on azoxymethane (AOM)-induced colon tumorigenesis. Male Ang II type 2 receptor gene-disrupted (AT(2)-null) mice with a 129/Ola and C57BL/6J genetic background, AT(2)-null mice with an SWR/J genetic background, and their corresponding control wild type mice were treated once a week with AOM (10 mg/kg, i.p., 4 consecutive weeks) or saline vehicle. All mice were killed 23-26 weeks after the initial injection of AOM, and tumor burdens were examined. AOM treatment caused the development of colon tumors in all wild type control mice regardless of genetic background (100% tumor prevalence), but only one tumor was present in AT(2)-null mice with a 129/Ola and C57BL/6J genetic background (11.1% tumor prevalence). Although the introduction of the AOMsusceptible SWR/J genetic background induced AOM susceptibility in AT(2) null mice, the tumor multiplicity (6.3) and tumor size (19.8 +/- 3.0 mm(3)) were significantly smaller than those in wild type mice (multiplicity, 12.0 and size, 36.8 +/- 3.2 mm(3)). AOM efficiently downregulated cytochrome P450 2E1 (CYP2E1) in the liver of wild type mice significantly more than in AT(2)-null mice. The levels of DNA methyl adducts formed in wild type mouse colon epithelium by AOM treatment were also significantly higher than in AT(2)-null mice. These results imply that the AT(2) receptor functions to augment AOM-induced downregulation of CYP2E1 expression in the liver, and thus increases AOM-induced tumorigenesis in the colon. The AT(2) receptor function in the liver may be a potential determinant of tumor susceptibility in chemical carcinogen-induced colon tumorigenesis.
Department of Biochemistry, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA.
Tetsuo
T
Takagi
Yuichiro
Y
Nakano
Susumu
S
Takekoshi
Tadashi
T
Inagami
Masaaki
M
Tamura
D000818:Animals; D001397:Azoxymethane; D015153:Blotting, Western; D002273:Carcinogens; D003106:Colon / Q000187:drug effects* / Q000201:enzymology*; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D003433:Crosses, Genetic; D019392:Cytochrome P-450 CYP2E1 / Q000172:deficiency / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D015536:Down-Regulation; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D005260:Female; D005838:Genotype; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002273:Carcinogens; D018736:DNA Adducts; D017931:DNA Primers; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D019392:Cytochrome P-450 CYP2E1; D010450:Endopeptidases; C047491:angiotensin-producing serum enzyme II; D001397:Azoxymethane