Cyclovirobuxine D induces autophagy-associated cell death via the Akt/mTOR pathway in MCF-7 human breast cancer cells.
Autophagy is a highly regulated and multi-step biological process that serves to remove damaged cytoplasmic components and organelles. It has been suggested that the activation of autophagy may be a promising therapeutic strategy for cancer treatment by triggering cell death. In this study, we reported that cyclovirobuxine D (CVB-D), an alkaloid component in a traditional Chinese herb, could induce autophagy in the MCF-7 human breast cancer cell line. CVB-D inhibited the viability of MCF-7 cells in a concentration- and time-dependent manner. Activation of autophagy was characterized by transmission electron microscopy, monodansylcadaverine staining, and expression of autophagy marker microtubule-associated protein 1 light chain 3 (LC3). After CVB-D treatment, a clear accumulation of autophagosomes was observed accompanied with elevated LC3 fluorescent puncta. Western blot analysis revealed that CVB-D significantly promoted the conversion from LC3-I to LC3-II and the expression of autophagy-related protein 5 (ATG5), which are both essential for autophagosome formation. On the other hand, CVB-D-induced autophagy and decrease in cell viability could be blocked by 3-methyladenine, a well-established autophagy inhibitor. Moreover, CVB-D attenuated the phosphorylation of Akt and mTOR, two pivotal suppressors in autophagy pathways. These findings shed new light on the pharmacological actions and mechanism of CVB-D and may support the potential utility of autophagy inducers in cancer treatment.
Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, China.
Jing
J
Lu
Duanping
D
Sun
Si
S
Gao
Ying
Y
Gao
Jiantao
J
Ye
Peiqing
P
Liu
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D000071187:Autophagy-Related Protein 5; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D058990:Molecular Targeted Therapy; D010766:Phosphorylation / Q000187:drug effects; D008517:Phytotherapy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; D004365:Drugs, Chinese Herbal; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; C025946:3-methyladenine; C032939:cyclovirobuxine D; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000225:Adenine