Metformin Enhances the Therapy Effects of Anti-IGF-1R mAb Figitumumab to NSCLC.

Hongxin Cao,Jun Xu,Xiao Qu,Hongchang Shen,Jiajun Du,Linhai Zhu,Qi Liu,Wei Dong

doi:10.1038/srep31072

Abstract

The insulin-like growth factor (IGF) signaling system plays a critical role in tumorigenesis, highlighting the potential of targeting IGF-1R as an anti-cancer therapy. Although multiple anti-IGF-1R monoclonal antibody (mAb) drugs have been developed, challenges remain in the validation of the therapeutic effects and understanding the molecular mechanism of these mAbs. Herein, we conducted a study to validate the effect of Figitumumab (CP), an anti-IGF-1R mAb, in a panel of non-small cell lung cancer (NSCLC) cell lines. We found all tested cell lines were sensitive to CP, and CP could block IGF-1R and the downstream PI3K/AKT pathway activation. Unexpectedly, we found CP could activate ERK signaling pathway in IGF-1R kinase independent manner, which we further verified was mainly mediated by β-arrestin2. We also investigated the anti-tumor effect of metformin alone as well as its combination with CP to target NSCLC. Metformin could target IGF-1R signaling pathway by attenuating PI3K/AKT and MEK/ERK signaling pathways and down-regulating IGF-1R. Finally, we found that combining metformin with CP could further induce IGF-1R down-regulation and was more effective to target NSCLC cells. Our data suggests the combining of metformin with CP has additive therapeutic value against NSCLC.

Highlights

Metformin (1, 1-dimethylbiguanide) is drawing increasing attention for its potential anti-neoplastic effects
insulin-like growth factor (IGF)-1R was expressed in all tested non-small cell lung cancer (NSCLC) cell lines, the exact expression level was variable, with A549 and PC-9 displaying the highest and lowest levels, respectively
IGF-1 could induce IGF-1R phosphorylation and activation of downstream RAS/RAF/MEK/ERK and PI3K/AKT signaling pathways in most cell lines, and the level of activation was generally correlated with the amount of IGF-1R in the cell. These results suggested that IGF-1R signaling pathway was responsive in all the cell lines we used

Summary

Results

Sensitivity to CP treatment in NSCLC cell lines. Firstly, we investigated the IGF-1R expression level in a panel of NSCLC cell lines, including A549, SK-MES-1, H520, SPC-A-1, H1975 and PC-9 (Fig. 1a). Our result suggested that CP and metformin have additive therapeutic effects to target NSCLC cell lines Even though both CP and metformin target IGF-1R signaling pathway, the combination might further inhibit IGF-1R activation, and/or either metformin or CP have additional anti-tumor effects that are not overlapped with each other. To further elucidate the additive therapeutic effects of CP and metformin, we tried to check the IGF-1R expression level after drug treatment in NSCLC cell lines. Β-arrestin[2] mRNA level was higher in tumor tissues than normal tissues (p < 0.001) (Fig. 6b), suggesting the active of β-arrestin[2] in NSCLC

Discussion

Conclusion

Materials and Methods