title: Identification of novel caspase/autophagy-related gene switch to cell fate decisions in breast cancers.
abstract: OBJECTIVE
  Caspases, a family of cysteine proteases with unique substrate specificities, contribute to apoptosis, whereas autophagy-related genes (ATGs) regulate cytoprotective autophagy or autophagic cell death in cancer. Accumulating evidence has recently revealed underlying mechanisms of apoptosis and autophagy; however, their intricate relationships still remain to be clarified. Identification of caspase/ATG switches between apoptosis and autophagy may address this problem.
  
  
  METHODS
  Identification of caspase/ATG switches was carried out using a series of elegant systems biology & bioinformatics approaches, such as network construction, hub protein identification, microarray analyses, targeted microRNA prediction and molecular docking.
  
  
  RESULTS
  We computationally constructed the global human network from several online databases and further modified it into the basic caspase/ATG network. On the basis of apoptotic or autophagic gene differential expressions, we identified three molecular switches [including androgen receptor, serine/threonine-protein kinase PAK-1 (PAK-1) and mitogen-activated protein kinase-3 (MAPK-3)] between certain caspases and ATGs in human breast carcinoma MCF-7 cells. Subsequently, we identified microRNAs (miRNAs) able to target androgen receptor, PAK-1 and MAPK-3, respectively. Ultimately, we screened a range of small molecule compounds from DrugBank, able to target the three above-mentioned molecular switches in breast cancer cells.
  
  
  CONCLUSIONS
  We have systematically identified novel caspase/ATG switches involved in miRNA regulation, and predicted targeted anti-cancer drugs. These findings may uncover intricate relationships between apoptosis and autophagy and thus provide further new clues towards possible cancer drug discovery.
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
authors.forename: L-L
authors.initials: LL
authors.lastname: Fu
authors.forename: Y
authors.initials: Y
authors.lastname: Yang
authors.forename: H-L
authors.initials: HL
authors.lastname: Xu
authors.forename: Y
authors.initials: Y
authors.lastname: Cheng
authors.forename: X
authors.initials: X
authors.lastname: Wen
authors.forename: L
authors.initials: L
authors.lastname: Ouyang
authors.forename: J-K
authors.initials: JK
authors.lastname: Bao
authors.forename: Y-Q
authors.initials: YQ
authors.lastname: Wei
authors.forename: B
authors.initials: B
authors.lastname: Liu
mesh_terms: D001343:Autophagy / Q000187:drug effects / Q000235:genetics*; D001665:Binding Sites; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D030541:Databases, Genetic; D005260:Female; D005812:Genes, Switch / Q000235:genetics; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D062105:Molecular Docking Simulation; D020411:Oligonucleotide Array Sequence Analysis; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D011355:Prodrugs; D011944:Receptors, Androgen; D054462:p21-Activated Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020169:Caspases