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 α (ERα) between two types of breast cancer cells, It is possibly suggested that CPT inhibits mTOR pathway dependent on ERα in breast cancer. CPT could significantly inhibit cell proliferation of ERα-positive cancer cells, whereas ERα-negative cancer cells are insensitive to CPT. The molecular docking results indicated that CPT has a high affinity with ERα, 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 shERα for silencing ERα 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 ERα is required for CPT inhibition of mTOR signalling. Overall, CPT inhibition of mTOR is dependent on ERα in breast cancer and should be a potential anti-oestrogen agent and a natural adjuvant for application in endocrine resistance therapy.

Keywords: breast cancer; cryptotanshinone; insulin receptor substrate 1; mammalian target of rapamycin; oestrogen receptor α.