Supplementation with branched-chain amino acids inhibits azoxymethane-induced colonic preneoplastic lesions in male C57BL/KsJ-db/db mice.
OBJECTIVE
Obesity and related metabolic abnormalities, including insulin resistance and activation of the insulin-like growth factor (IGF)/IGF-I receptor (IGF-IR) axis, are risk factors for colon cancer. Supplementation with branched-chain amino acids (BCAA) reduces the risk of liver cancer in cirrhotic patients who are obese, and this has been associated with an improvement of insulin resistance. The present study examined the effects of BCAA on the development of azoxymethane (AOM)-initiated colonic premalignant lesions in C57BL/KsJ-db/db (db/db) mice that were obese and had hyperinsulinemia.


METHODS
Male db/db mice were given 4 weekly s.c. injections of AOM (15 mg/kg of body weight) and then they were fed a diet containing 3.0% BCAA or casein, a nitrogenc content-matched control diet, for 7 weeks.


RESULTS
Feeding with BCAA caused a significant reduction in the number of total aberrant crypt foci and beta-catenin accumulated crypts, both of which are premalignant lesions of the colon, compared with the control diet-fed groups. BCAA supplementation caused a marked decrease in the expression of IGF-IR, the phosphorylated form of IGF-IR, phosphorylated glycogen synthase kinase 3beta, phosphorylated Akt, and cyclooxygenase-2 proteins on the colonic mucosa of AOM-treated mice. The serum levels of insulin, IGF-I, IGF-II, triglyceride, total cholesterol, and leptin were also decreased by supplementation with BCAA.


CONCLUSIONS
BCAA supplementation in diet improves insulin resistance and inhibits the activation of the IGF/IGF-IR axis, thereby preventing the development of colonic premalignancies in an obesity-related colon cancer model that was also associated with hyperlipidemia and hyperinsulinemia. BCAA, therefore, may be a useful chemoprevention modality for colon cancer in obese people.
Shimizu
Masahito
M
Department of Medicine and Tumor Pathology, Gifu University Graduate School of Medicine, Japan. shimim-gif@umin.ac.jp
Shirakami
Yohei
Y
Iwasa
Junpei
J
Shiraki
Makoto
M
Yasuda
Yoichi
Y
Hata
Kazuya
K
Hirose
Yoshinobu
Y
Tsurumi
Hisashi
H
Tanaka
Takuji
T
Moriwaki
Hisataka
H
D000597:Amino Acids, Branched-Chain / Q000627:therapeutic use*; D000818:Animals; D001397:Azoxymethane / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019587:Dietary Supplements; D007328:Insulin / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D011230:Precancerous Conditions / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051176:beta Catenin / Q000378:metabolism
D000597:Amino Acids, Branched-Chain; D002273:Carcinogens; D007328:Insulin; D018809:Proliferating Cell Nuclear Antigen; D017527:Receptor, IGF Type 2; D051176:beta Catenin; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; D001397:Azoxymethane