Cryptotanshinone inhibition of mammalian target of rapamycin pathway is dependent on oestrogen receptor alpha in breast cancer.

ABSTRACT: Cryptotanshinone (CPT) has been demonstrated to inhibit proliferation and mammalian target of rapamycin (mTOR) pathway in MCF-7 breast cancer cells. However, the same results are unable to be repeated in MDA-MB-231 cells. Given the main difference of oestrogen receptor ? (ER?) between two types of breast cancer cells, It is possibly suggested that CPT inhibits mTOR pathway dependent on ER? in breast cancer. CPT could significantly inhibit cell proliferation of ER?-positive cancer cells, whereas ER?-negative cancer cells are insensitive to CPT. The molecular docking results indicated that CPT has a high affinity with ER?, and the oestrogen receptor element luciferase reporter verified CPT distinct anti-oestrogen effect. Furthermore, CPT inhibits mTOR signalling in MCF-7 cells, but not in MDA-MB-231 cells, which is independent on binding to the FKBP12 and disrupting the mTOR complex. Meanwhile, increased expression of phosphorylation AKT and insulin receptor substrate (IRS1) induced by insulin-like growth factor 1 (IGF-1) was antagonized by CPT, but other molecules of IGF-1/AKT/mTOR signalling pathway such as phosphatase and tensin homolog (PTEN) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) were negatively affected. Finally, the MCF-7 cells transfected with shER? for silencing ER? show resistant to CPT, and p-AKT, phosphorylation of p70 S6 kinase 1 (p-S6K1) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1) were partially recovered, suggesting ER? is required for CPT inhibition of mTOR signalling. Overall, CPT inhibition of mTOR is dependent on ER? in breast cancer and should be a potential anti-oestrogen agent and a natural adjuvant for application in endocrine resistance therapy.

SUBMITTER: Pan Y 

PROVIDER: S-EPMC5571522 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature