title: Targeting the JNK signaling pathway potentiates the antiproliferative efficacy of rapamycin in LS174T colon cancer cells.
abstract: BACKGROUND
  Targeting the mTOR signaling pathway with rapamycin in cancer therapy has been less successful than expected due in part to the removal of a negative feedback loop resulting in the over-activation of the PI3K/Akt signaling pathway. As the c-Jun N-terminal kinase (JNK) signaling pathway has been found to be a functional target of PI3K, we investigate the role of JNK in the anticancer efficacy of rapamycin.
  
  
  METHODS
  The colon cancer cell line LS174T was treated with rapamycin and JNK phosphorylation was analyzed by Western Blot. Overexpression of a constitutively negative mutant of JNK in LS174T cells or treatment of LS174T cells with the JNK inhibitor SP600125 were used to determine the role of JNK in rapamycin-mediated tumor growth inhibition.
  
  
  RESULTS
  Treatment of LS174T cells with rapamycin resulted in the phosphorylation of JNK as observed by Western Blot. The expression of a negative mutant of JNK in LS174T cells or treatment of LS174T cells with SP600125 enhanced the antiproliferative effects of rapamycin. In addition, in vivo, the antitumor activity of rapamycin was potentiated on LS174T tumor xenografts that expressed the dominant negative mutant of JNK.
  
  
  CONCLUSIONS
  Taken together, these results show that rapamycin-induced JNK phosphorylation and activation reduces the antitumor efficacy of rapamycin in LS174T cells.
authors.affiliation: Department of Visceral Surgery, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Benoit
authors.forename: Anne
authors.initials: A
authors.lastname: Dormond-Meuwly
authors.forename: Nicolas
authors.initials: N
authors.lastname: Demartines
authors.forename: Olivier
authors.initials: O
authors.lastname: Dormond
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D023421:Models, Animal; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000873:Anthracenes; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D020123:Sirolimus