Open AccessThe Activation of ERK1/2 and JNK MAPK Signaling by Insulin/IGF-1 Is Responsible for the Development of Colon Cancer with Type 2 Diabetes Mellitus
Author(s) -
Jia An Teng,
San Gang Wu,
Jia Xin Chen,
Qiang Li,
Fang Peng,
Zhou Zhu,
Jian Qin,
Zhenyu He
Publication year - 2016
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0149822
Subject(s) - insulin , endocrinology , medicine , insulin like growth factor , kinase , colorectal cancer , mapk/erk pathway , insulin receptor , cancer , cancer research , insulin resistance , biology , growth factor , receptor , microbiology and biotechnology
Previous studies showed that type 2 diabetes mellitus (T2DM) is linked to increased risk of developing colon cancer. Insulin and insulin-like growth factor 1 (IGF-1) are increased in patients with T2DM. The increased insulin and IGF-1 may be responsible for the developing of colon cancer. In this study, we investigated the effects and mechanisms of insulin and IGF-1 in colon cancer development in vitro and in vivo . Insulin and IGF-1 alone or together elevated proliferation and reduced apoptosis in colon cancer MC38 cells. Meanwhile, insulin and IGF-1 promoted the phosphorylation of extracellular-signal regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK). Treatment with ERK1/2 or JNK inhibitor in the presence of insulin and IGF-1 significantly decreased B-cell lymphoma 2 (Bcl-2) and increased Bcl-2-associated X protein (Bax) expression and finally increased apoptosis and inhibited the proliferation. Accelerative colon tumor growth was found in a mouse model of T2DM with db/db mice which got high level of endogenous insulin and IGF-1. Furthermore, the inhibition of ERK1/2 or JNK suppressed the development of colon tumor in vivo . These results suggest that the activation of ERK1/2 and JNK signaling by insulin and IGF-1, at least in part, is responsible for the development of colon cancer with T2DM.