Obesity and drug resistance: insulin confers resistance of melanoma cells to chemotherapeutic drugs via activation of PI3K/Akt pathway

Jiezhong Chen, Mengna Chi and Xu Dong Zhang

Introduction: Obesity is associated with increased incidence and poor prognosis of many cancers including melanoma. However, it is not known how obesity causes poor prognosis of melanoma. We hypothesise that altered cancer risk factors in obesity such as insulin and leptin could be mediators for drug resistance to chemotherapeutic agents used in melanoma via activated PI3K/Akt signalling pathway.
Objectives: In this study we tested the effect of insulin on Dacabzine-induced cytotoxicity in mouse melanoma cell line B16. The effect of insulin on the response of human melanoma cells to various chemotherapeutic drugs and inhibitors against the RAF/MEK/ERK pathway was also studied in human melanoma cells:Mel-RM and Mel-RMu. We further examined the role of the PI3K/Akt pathway in the insulin-induced drug resistance and used dual inhibitors of PI3K and mTOR to overcome insulin-inuced drug resistance.
Methods: The effect of insulin on chemotherapeutic agents-induced cytotoxicity was tested by pre-incubation of melanoma cells with 1μM insulin followed by addition of chemotherapeutic agents and insulin. Cytotoxicity was determined by MTS assay. The activity of the PI3K/Akt pathway was indicated by phosphorylated Akt levels determined by Western blotting.
Results: Dacabzine produced dose-dependent cytotoxicity on B16 at concentrations of 12.5, 25, 50, 100ug/ml. Addition of 1μM insulin into B16 cells decreased the cytotoxicity of Dacabzine-induced cytotoxicity significantly. Dual inhibitors of PI3K and mTOR abolished such an effect of insulin. Similarly, inhibition of PI3K/Akt/mTOR attenuates insulin-induced resistance of human melanoma cells to chemotherapeutic drugs or BRAF/MEK inhibitors. Western blotting showed that pAkt were highly activated by insulin and inhibited by dual inhibitors of PI3K and mTOR.
Conclusions: Insulin decreases drug efficacy of chemotherapeutic agents in melanoma cells, which could be mediated by the PI3K/Akt pathway. The insulin-induced drug resistance is overcome by dual inhibitors of PI3K and mTOR.