title: 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.
authors.affiliation: School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.|Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Oncology, Nanjing First Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Shi
authors.affiliation: School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Wenting
authors.initials: W
authors.lastname: Ni
authors.affiliation: School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Siliang
authors.initials: S
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Zhonghong
authors.initials: Z
authors.lastname: Wei
authors.affiliation: School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.|Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Aiyun
authors.initials: A
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.|Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Wenxing
authors.initials: W
authors.lastname: Chen
authors.affiliation: School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.|Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Lu
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D062105:Molecular Docking Simulation; D010616:Phenanthrenes / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D047628:Estrogen Receptor alpha; C583557:IGF1 protein, human; D010616:Phenanthrenes; C037886:cryptotanshinone; D007334:Insulin-Like Growth Factor I; D058570:TOR Serine-Threonine Kinases
keywords: breast cancer; cryptotanshinone; insulin receptor substrate 1; mammalian target of rapamycin; oestrogen receptor α