Silibinin-induced apoptosis of breast cancer cells involves mitochondrial impairment

• Published in: Archives of biochemistry and biophysics 2019-08, Vol.671, p.42-51
• Main Authors: Si, Lingling, Liu, Weiwei, Hayashi, Toshihiko, Ji, Yachao, Fu, Jianing, Nie, Yuheng, Mizuno, Kazunori, Hattori, Shunji, Onodera, Satoshi, Ikejima, Takashi
• Format: Article
• Language: English
• Subjects: Amino Acid Chloromethyl Ketones - pharmacology; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Cell Line, Tumor; Dynamins - metabolism; GTP Phosphohydrolases - metabolism; Humans; Membrane Potential, Mitochondrial - drug effects; Membrane Proteins - metabolism; Mitochondria; Mitochondria - drug effects; Mitochondria - pathology; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial Dynamics - drug effects; Mitochondrial fragmentation; Mitochondrial Membrane Transport Proteins - metabolism; Mitochondrial Proteins - metabolism; Organelle Biogenesis; Quinazolinones - pharmacology; Silibinin; Silybin - pharmacology
• ISSN: 0003-9861; 1096-0384
• DOI: 10.1016/j.abb.2019.05.009

Mitochondria are dynamically regulated by fission and fusion processes. Silibinin induces apoptosis of MCF-7 and MDA-MB-231 human breast cancer cells. However, whether or not mitochondria dysfunction is involved in the apoptosis induction with silibinin of both types of the cells remains unknown. We here report that silibinin decreases the mitochondrial mass in terms of MitoTracker Green staining in both breast cancer cells. Silibinin induces morphological changes of mitochondria from oval to truncated or fragmented shapes accordingly. Condensed crests are observed in mitochondria by transmission electron microscopy. Silibinin causes mitochondrial membrane potential reduced. The expression of mitochondrial fission-associated proteins including dynamin-related protein 1 (DRP1) is up-regulated, whereas expression of the mitochondrial fusion-associated proteins, optic atrophy 1 and mitofusin 1, is down-regulated. In addition, silibinin treatment down-regulates ATP content as well as the levels of mitochondrial biogenesis-regulators including mitochondrial transcription factor A, peroxisome proliferator-activated receptor gamma coactivator 1 and nuclear respiratory factor 2. Moreover, treatments with DRP1 inhibitor, mdivi-1, or with DRP1-targetted siRNA efficiently prevent silibinin-induced apoptosis in the breast cancer cells, whereas inhibition of DRP1 phosphorylation with staurosporine increases apoptosis furthermore. Taken together, we conclude that silibinin impairs mitochondrial dynamics and biogenesis, leading to apoptosis of MCF-7 and MDA-MB-123 cells.