title: 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.
authors.affiliation: a Department of Urology , Shanghai Jiao Tong University Affiliated Sixth People's Hospital , Shanghai , China.
authors.forename: Binqiang
authors.initials: B
authors.lastname: Tian
authors.affiliation: b Department of Gynaecology and Obstetrics , Shanghai Pudong Hospital, Fudan University Pudong Medical Center , Shanghai , China.
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: a Department of Urology , Shanghai Jiao Tong University Affiliated Sixth People's Hospital , Shanghai , China.
authors.forename: Tao
authors.initials: T
authors.lastname: Liang
authors.affiliation: a Department of Urology , Shanghai Jiao Tong University Affiliated Sixth People's Hospital , Shanghai , China.
authors.forename: Xuxiao
authors.initials: X
authors.lastname: Ye
authors.affiliation: a Department of Urology , Shanghai Jiao Tong University Affiliated Sixth People's Hospital , Shanghai , China.
authors.forename: Zuowei
authors.initials: Z
authors.lastname: Li
authors.affiliation: a Department of Urology , Shanghai Jiao Tong University Affiliated Sixth People's Hospital , Shanghai , China.
authors.forename: Dongliang
authors.initials: D
authors.lastname: Yan
authors.affiliation: a Department of Urology , Shanghai Jiao Tong University Affiliated Sixth People's Hospital , Shanghai , China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Fu
authors.affiliation: a Department of Urology , Shanghai Jiao Tong University Affiliated Sixth People's Hospital , Shanghai , China.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D003474:Curcumin / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000037:antagonists & inhibitors* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014158:Transcription, Genetic; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
chemical_list: D003474:Curcumin; D007335:Insulin-Like Growth Factor II; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C035170:IGF2 protein, human; C546842:MTOR protein, human
keywords: Curcumin; IGF2; PI3K/AKT/mTOR; urothelial tumor