title: Apoptosis signal-regulating kinase 1-thioredoxin complex dissociation by capsaicin causes pancreatic tumor growth suppression by inducing apoptosis.
abstract: OBJECTIVE
  In this study, we evaluated the effect of capsaicin on the interaction of redox-sensitive thioredoxin (Trx)/apoptosis signal-regulating kinase 1 (ASK1) in pancreatic cancer cells.
  
  
  RESULTS
  Capsaicin treatment downregulated Trx and increased the phosphorylation (activation) of ASK1 at Thr845 and kinase activity in AsPC-1 and BxPC-3 cells. Capsaicin treatment also activated downstream effector molecules MKK4/7, caspase-9, and caspase-3. Antioxidants tiron or PEG-catalase blocked the activation of ASK1 cascade by capsaicin and protected the cells from apoptosis, indicating the involvement of reactive oxygen species in the activation of ASK1. Our results further revealed that Trx overexpression suppressed the effects of capsaicin, whereas ASK1 overexpression enhanced the apoptosis-inducing effects of capsaicin. β-mercaptoethanol, a reducing agent, blocked capsaicin-mediated activation of ASK1, indicating that Trx-ASK1 complex exists and requires reducing conditions in the cell. On the other hand, the Trx inhibitor (1-chloro-2-4-dinitrobenzene) increased capsaicin-induced ASK1 kinase activity, suggesting that Trx inhibition by capsaicin is essential for ASK1 activation. Oral administration of 5 mg capsaicin/kg body weight substantially suppressed the growth of tumors in xenograft and orthotopic mouse model. Tumors from capsaicin-treated mice showed reduced levels of Trx, increased phosphorylation of ASK1 at Thr845, and cleavage of caspase-3 and poly (ADP-ribose) polymerase.
  
  
  METHODS
  Our results for the first time demonstrated a new perspective that Trx-ASK1 complex can be targeted by capsaicin in pancreatic cancer.
  
  
  CONCLUSIONS
  Capsaicin reduces Trx expression and dissociates Trx-ASK1 complex resulting in the activation of ASK1 and downstream effectors leading to apoptosis in pancreatic tumor cells in vitro and in vivo.
authors.affiliation: Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.
authors.forename: Kartick C
authors.initials: KC
authors.lastname: Pramanik
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Srivastava
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002211:Capsaicin / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D017382:Reactive Oxygen Species; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D013879:Thioredoxins; D048848:MAP Kinase Kinase Kinase 5; D002211:Capsaicin