title: Plant cyclopeptide RA-V kills human breast cancer cells by inducing mitochondria-mediated apoptosis through blocking PDK1-AKT interaction.
abstract: In the present paper, we examined the effects of a natural cyclopeptide RA-V on human breast cancer cells and the underlying mechanisms. RA-V significantly inhibited the growth of human breast cancer MCF-7, MDA-MB-231 cells and murine breast cancer 4T1 cells. In addition, RA-V triggered mitochondrial apoptotic pathway which was indicated by the loss of mitochondrial membrane potential, the release of cytochrome c, and the activation of caspase cascade. Further study showed that RA-V dramatically inhibited phosphorylation of AKT and 3-phosphoinositide dependent protein kinase 1 (PDK1) in MCF-7 cells. Moreover, RA-V disrupted the interaction between PDK1 and AKT in MCF-7 cells. Furthermore, RA-V-induced apoptosis could be enhanced by phosphatidylinositol 3-kinase inhibitor or attenuated by over-expression of AKT in all the three kinds of breast cancer cells. Taken together, this study shows that RA-V, which can induce mitochondria-mediated apoptosis, exerts strong anti-tumor activity against human breast cancer. The underlying anti-cancer mechanism of RA-V is related to the blockage of the interaction between PDK1 and AKT.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Han Kou Road, Nanjing, China.
authors.forename: Xian-Ying
authors.initials: XY
authors.lastname: Fang
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Jun-Ting
authors.initials: JT
authors.lastname: Fan
authors.forename: Ran
authors.initials: R
authors.lastname: Song
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Yan-Hong
authors.initials: YH
authors.lastname: Gu
authors.forename: Guang-Zhi
authors.initials: GZ
authors.lastname: Zeng
authors.forename: Yan
authors.initials: Y
authors.lastname: Shen
authors.forename: Xue-Feng
authors.initials: XF
authors.lastname: Wu
authors.forename: Ning-Hua
authors.initials: NH
authors.lastname: Tan
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xu
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D025941:Protein Interaction Mapping; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; D010456:Peptides, Cyclic; D010936:Plant Extracts; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; C043547:RA V; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt