The role of P-glycoprotein in intestinal tumorigenesis: disruption of mdr1a suppresses polyp formation in Apc(Min/+) mice.
P-glycoprotein (P-gp) mediates the active transport of various substrates including xenobiotics, and it thus has a protective function in various cell types and tissues/organs including the intestinal epithelium. However, whether or not P-gp plays a positive role in the intestinal tumorigenesis is unclear. We have introduced disrupted alleles of the murine P-gp gene, mdr1a, into Apc(Min/+) mice to evaluate whether P-gp plays any role in intestinal carcinogenesis. Spontaneously occurring DNA damage was significantly increased in both the small and large intestine of mdr1a(-/-), Apc(Min/+) mice compared with mdr1a(+/+), Apc(Min/+) mice. Furthermore, we observed active proliferation and rapid migration/disappearance of enterocytes in the intestine of the compound mice deficient in mdr1a. Finally, we found that the number of polyps and cancers was markedly decreased in mdr1a(-/-), Apc(Min/+) mice (P=0.0016). P-gp thus appears to play a positive role during intestinal tumorigenesis.
Mochida
Yasushi
Y
Department of Medical Biochemistry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Taguchi
Ken-ichi
K
Taniguchi
Shuichi
S
Tsuneyoshi
Masazumi
M
Kuwano
Hiroyuki
H
Tsuzuki
Teruhisa
T
Kuwano
Michihiko
M
Wada
Morimasa
M
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000502:physiology*; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D001973:Bromodeoxyuridine; D002455:Cell Division; D002465:Cell Movement; D004249:DNA Damage; D018450:Disease Progression; D018432:Drug Resistance, Multiple / Q000235:genetics; D020895:Enterocytes / Q000378:metabolism / Q000473:pathology; D005260:Female; D017491:Genes, APC / Q000502:physiology*; D007124:Immunoenzyme Techniques; D007413:Intestinal Mucosa / Q000378:metabolism; D007417:Intestinal Polyps / Q000473:pathology / Q000517:prevention & control*; D007422:Intestines / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; C095122:multidrug resistance protein 3; D001973:Bromodeoxyuridine