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.
Highlights
In the past decades, due to the rapid economic growth and changes in lifestyle in China, the incidence and cases of diabetes have been rising rapidly
We speculated that insulin or insulinlike growth factor 1 (IGF-1) got the same effects on MC38 cells, a mouse derived colon cancer cell line
We found that either insulin or IGF-1 promoted the expansion of MC38 cells in vitro (Fig 1A)
Summary
Due to the rapid economic growth and changes in lifestyle in China, the incidence and cases of diabetes have been rising rapidly. T2DM is associated with hyperinsulinemia and elevated insulinlike growth factor 1 (IGF-1). An important growth factor acting as a cell mitogen, when at high concentrations increase the risk of colon cancer by promoting growth of tumors [10]. The insulin treatment may further elevate risk for colon cancer in patients with T2DM [11]. Previous studies showed an association between elevated IGF-1 and the risks of colon cancer [14, 15]. Previous studies showed that MAPK signal, which acts as downstream of insulin and IGF-1 proliferative signaling, plays a role in the proliferation of various cancers, including breast, colon and prostate cancer [18,19,20]. Due to the lack of ideal colon cancer model with T2DM, it is still not clear how does this signal regulate the proliferation of colon cancer in a T2DM environment
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