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

• Published in: PloS one 2016-02, Vol.11 (2), p.e0149822-e0149822
• Main Authors: Teng, Jia-An, Wu, San-Gang, Chen, Jia-Xin, Li, Qiang, Peng, Fang, Zhu, Zhou, Qin, Jian, He, Zhen-Yu
• Format: Article
• Language: English
• Subjects: Activation; Animals; Apoptosis; Apoptosis - drug effects; B-cell lymphoma; BAX protein; Bcl-2 protein; bcl-2-Associated X Protein - genetics; bcl-2-Associated X Protein - metabolism; Bcl-x protein; Beta cells; Biology and Life Sciences; Blood Glucose - drug effects; c-Jun protein; Cancer; Cancer therapies; Cell cycle; Cell Cycle - drug effects; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Cellular signal transduction; Colon; Colon cancer; Colonic Neoplasms - etiology; Colonic Neoplasms - metabolism; Colorectal cancer; Complications and side effects; Development and progression; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Extracellular signal-regulated kinase; Genetic aspects; Health aspects; Health risks; Hormones; Inhibition; Insulin; Insulin - metabolism; Insulin - pharmacology; Insulin-like growth factor I; Insulin-Like Growth Factor I - metabolism; Insulin-Like Growth Factor I - pharmacology; Insulin-like growth factors; JNK Mitogen-Activated Protein Kinases - genetics; JNK Mitogen-Activated Protein Kinases - metabolism; JNK protein; Kinases; Lymphoma; Male; MAP kinase; MAP Kinase Signaling System - drug effects; Medical research; Medicine and Health Sciences; Metabolism; Mice; Oncology; Phosphorylation; Physiological aspects; Proteins; Research and Analysis Methods; Risk factors; Rodents; Studies; Transcription factors; Type 2 diabetes
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0149822

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.