title: The 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.
abstract: 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.
authors.affiliation: Department of Cadre Medicine, Division of Endocrinology and Metabolism, People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.
authors.forename: Jia-An
authors.initials: JA
authors.lastname: Teng
authors.affiliation: Department of Radiation Oncology, Xiamen Cancer Center, the First affiliated Hospital of Xiamen University, Xiamen, China.
authors.forename: San-Gang
authors.initials: SG
authors.lastname: Wu
authors.affiliation: Department of Radiation Oncology of Clinical Cancer Center, the People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.
authors.forename: Jia-Xin
authors.initials: JX
authors.lastname: Chen
authors.affiliation: Organ Transplantation Center, Department of Surgery, the Second Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Radiation Oncology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Peng
authors.affiliation: Department of Gastrointestinal and Peripheral Vascular Surgery, the People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Radiation Oncology of Clinical Cancer Center, the People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Qin
authors.affiliation: Sun Yat-sen University Cancer Center, State Key laboratory of Oncology in South China, Department of Radiation Oncology, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors.forename: Zhen-Yu
authors.initials: ZY
authors.lastname: He
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000209:etiology* / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; D051028:bcl-2-Associated X Protein; D007334:Insulin-Like Growth Factor I; D048031:JNK Mitogen-Activated Protein Kinases