Inhibition of insulin-like growth factor 1 receptor signaling enhanced silibinin-induced activation of death receptor and mitochondrial apoptotic pathways in human breast cancer MCF-7 cells.
Silibinin, which had been used as a hepatoprotectant, was shown to have anticancer activity. In this study we investigated the mechanisms of silibinin-induced apoptosis in human breast cancer MCF-7 cells. Expressions of Fas ligand (FasL), Fas-associated death domain protein (FADD), and Bax were significantly up-regulated in silibinin-treated cells, whilst silibinin induced a conspicuous translocation of Bax to mitochondria and release of cytochrome c to the cytosol. Therefore, both the extrinsic Fas death receptor and intrinsic mitochondrial death pathways played essential roles in silibinin-induced apoptosis. It was also found that silibinin markedly decreased protein expression of SIRT1, a mammalian homologue of yeast Sir2, which was proved to have a role in sequestering Bax away from mitochondria. Insulin-like growth factor 1 receptor (IGF-1R), a receptor tyrosine kinase with a crucial role in malignancy development, is expressed in most human primary breast carcinomas. Our results showed that silibinin-induced apoptosis was significantly reinforced by blocking IGF-1R signaling with tyrphostin AG1024, a specific inhibitor of IGF-1R autophosphorylation. Up-regulation of FADD, down-regulation of SIRT1 expression, and activation of the mitochondrial death pathway were apparently enhanced by AG1024 in the silibinin-treated MCF-7 cells.
Wang
Hong-Jun
HJ
China-Japan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang, China.
Tashiro
Shin-ichi
S
Onodera
Satoshi
S
Ikejima
Takashi
T
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001943:Breast Neoplasms / Q000473:pathology; D005260:Female; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D053218:Receptors, Death Domain / Q000378:metabolism*; D015398:Signal Transduction; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D053218:Receptors, Death Domain; D012838:Silymarin; D000077385:Silybin; D017526:Receptor, IGF Type 1