Curcumin inhibits urothelial tumor development by suppressing IGF2 and IGF2-mediated PI3K/AKT/mTOR signaling pathway

Abstract

We have previously reported that curcumin inhibits urothelial tumor development in a rat bladder carcinogenesis model. In this study, we report that curcumin inhibits urothelial tumor development by suppressing IGF2 and IGF2-mediated PI3K/AKT/mTOR signaling pathway. Curcumin inhibits IGF2 expression at the transcriptional level and decreases the phosphorylation levels of IGF1R and IRS-1 in bladder cancer cells and N-methyl-N-nitrosourea (MNU)-induced urothelial tumor tissue. Ectopic expression of IGF2 and IGF1R, but not IGF1, in bladder cancer cells restored this process, suggesting that IGF2 is a target of curcumin. Moreover, introduction of constitutively active AKT1 abolished the inhibitory effect of curcumin on cell proliferation, migration, and restored the phosphorylation levels of 4E-BP1 and S6K1, suggesting that curcumin functions via suppressing IGF2-mediated AKT/mTOR signaling pathway. In summary, our results reveal that suppressing IGF2 and IGF2-mediated PI3K/AKT/mTOR signaling pathway is one of the mechanisms of action of curcumin. Our findings suggest a new therapeutic strategy against human bladder cancer caused by aberrant activation of IGF2, which are useful for translational application of curcumin.

Keywords:

• Curcumin
• urothelial tumor
• IGF2
• PI3K/AKT/mTOR

Acknowledgements

This work was partly supported by grants from the Shanghai Municipal Commission of Health and Family Planning [grant No. 201440310] and Shanghai Sixth People’s Hospital East Campus Science Foundation [grant No.2013029].

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Compliance with ethical standards

Animal experiments were approved by the Animal Care and Use Committee of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital.

Disclosure statement

The authors declare that they have no competing interests.

Additional information

Funding

This work was partly supported by grants from the Shanghai Municipal Commission of Health and Family Planning [grant No. 201440310] and Shanghai Sixth People’s Hospital East Campus Science Foundation [grant No. 2013029].