Involvement of JNK pathway in the promotion of the early stage of colorectal carcinogenesis under high-fat dietary conditions.
OBJECTIVE
The molecular mechanisms underlying the promotion of colorectal carcinogenesis by a high-fat diet (HFD) remain unclear. We investigated the role of the insulin-signal pathway and the c-Jun N-terminal kinase (JNK) pathway, which reportedly play crucial roles in insulin resistance, during colorectal carcinogenesis in the presence of hyperinsulinaemia induced by a HFD.


METHODS
Azoxymethane-induced aberrant crypt foci formation and cell proliferation in the colonic epithelium were compared between mice fed a normal diet (ND) and mice fed a HFD. A western blot analysis was performed to elucidate the mechanism affecting colorectal carcinogenesis by a HFD.


RESULTS
The number of aberrant crypt foci and the colonic epithelial cell proliferative activity were significantly higher in the HFD group than in the ND group. While the plasma insulin level was significantly higher in the HFD group than in the ND group, a western blot analysis revealed the inactivation of Akt, which is located downstream of the insulin receptor, in the colonic epithelia of the HFD group. On the other hand, JNK activity was significantly higher in the HFD group than in the ND group. A JNK specific inhibitor significantly suppressed the increase in epithelial cell proliferation only under a HFD, but not under a ND.


CONCLUSIONS
Colonic cell proliferation was promoted via the JNK pathway in the presence of a HFD but not in the presence of a ND. This novel mechanism may explain the involvement of the JNK pathway in the effect of dietary fat intake on colon carcinogenesis.
Endo
H
H
3-9 Fuku-ura, Kanazawa-ku, Yokohama 236-0004, Japan; nakajima-tky@umin.ac.jp.
Hosono
K
K
Fujisawa
T
T
Takahashi
H
H
Sugiyama
M
M
Yoneda
K
K
Nozaki
Y
Y
Fujita
K
K
Yoneda
M
M
Inamori
M
M
Wada
K
K
Nakagama
H
H
Nakajima
A
A
D000818:Animals; D001397:Azoxymethane; D002273:Carcinogens; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D003106:Colon / Q000473:pathology; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D004041:Dietary Fats / Q000009:adverse effects*; D004195:Disease Models, Animal; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology; D007413:Intestinal Mucosa / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000502:physiology
D002273:Carcinogens; D004041:Dietary Fats; D007328:Insulin; D048670:MAP Kinase Kinase 4; D001397:Azoxymethane