title: Carvedilol suppresses migration and invasion of malignant breast cells by inactivating Src involving cAMP/PKA and PKCδ signaling pathway.
abstract: BACKGROUND
  Carvedilol (CAR) can inhibit cell growth and induce cell apoptosis in breast cancer in vitro. But it is still not known whether CAR affects the migration and invasion of breast cancer cells.
  
  
  OBJECTIVE
  To investigate the effects of CAR on migration and invasion of breast cancer cells and its corresponding signal pathways.
  
  
  METHODS
  Firstly, the invasive potential of breast cancer cells were investigated after incubation with CAR and/or norepinephrine (NE). If the invasive potential of breast cancer cells were inhibited by CAR, then the signal pathways related to migration and invasion were detected, such as Src, cyclic adenosine monohposphate (cAMP)/protein kinase A (PKA), etc.
  
  
  METHODS
  Membrane invasion culture system (MICS) chamber was used to measure the invasive and migratory potential of breast cancer cells. Western blot analysis and small interfering RNA (siRNA) transfection experiment were employed to determine the signal pathway adopted by CAR in suppressing migration and invasion of MDA-MB-231 and MCF-7 cells. cAMP-Glo and PKCδ kinase activity assay kit were used to measure cAMP and PKCδ activity, respectively, according to the manufacturer's instructions.
  
  
  METHODS
  Statistical differences between the mean values of control and experimental groups were determined using two-tailed, unpaired Student's t-tests.
  
  
  RESULTS
  CAR significantly decreased the potential of migration and invasion of breast cancer cells. CAR inhibited Src activation in MDA-MB-231 and MCF-7 cells through blocking beta or alpha adrenergic receptor (ADR), respectively. Furthermore, CAR suppressed the Src activation through different signaling pathways. Under treatment of CAR, cAMP/PKA-Src pathway was inhibited in MDA-MB-231 cells; but in MCF-7 cells, CAR mainly inhibited the PKCδ-Src pathway.
  
  
  CONCLUSIONS
  CAR was an anti-metastatic agent, which targets Src involving cAMP/PKA or PKCδ pathway in malignant breast cells.
authors.forename: Gao
authors.initials: G
authors.lastname: Dezong
authors.forename: Ma
authors.initials: M
authors.lastname: Zhongbing
authors.affiliation: Department of Breast Surgery, The Second Hospital of Shandong University, Jinan, Shandong, China.
authors.forename: Fu
authors.initials: F
authors.lastname: Qinye
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhigang
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000737:chemistry; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy*; D000081247:CSK Tyrosine-Protein Kinase; D002227:Carbazoles / Q000737:chemistry*; D000077261:Carvedilol; D016923:Cell Death; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D011412:Propanolamines / Q000737:chemistry*; D051745:Protein Kinase C-delta / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D002227:Carbazoles; D011412:Propanolamines; D034741:RNA, Small Interfering; D000077261:Carvedilol; D000242:Cyclic AMP; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D017868:Cyclic AMP-Dependent Protein Kinases; D051745:Protein Kinase C-delta