title: The serine-threonine kinase p90RSK is a new target of enzastaurin in follicular lymphoma cells.
abstract: OBJECTIVE
  Follicular lymphoma is the second most common non-Hodgkin's lymphoma and, despite the introduction of rituximab for its treatment, this disease is still considered incurable. Besides genetic alterations involving Bcl-2, Bcl-6 or c-Myc, follicular lymphoma cells often display altered B-cell receptor signalling pathways including overactive PKC and PI3K/Akt systems.
  
  
  METHODS
  The effect of enzastaurin, an inhibitor of PKC, was evaluated both in vitro on follicular lymphoma cell lines and in vivo on a xenograft murine model. Using pharmacological inhibitors and siRNA transfection, we determined the different signalling pathways after enzastaurin treatment.
  
  
  RESULTS
  Enzastaurin inhibited the serine-threonine kinase p90RSK which has downstream effects on GSK3β. Bad and p70S6K. These signalling proteins control follicular lymphoma cell survival and apoptosis; which accounted for the inhibition by enzastaurin of cell survival and its induction of apoptosis of follicular lymphoma cell lines in vitro. Importantly, these results were replicated in vivo where enzastaurin inhibited the growth of follicular lymphoma xenografts in mice.
  
  
  CONCLUSIONS
  The targeting of p90RSK by enzastaurin represents a new therapeutic option for the treatment of follicular lymphoma.
authors.affiliation: INSERM UMR1037-Centre de Recherche en Cancérologie de Toulouse, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France; ERL 5294 CNRS, BP3028, Hôpital Purpan, Toulouse, France; Institut Carnot Lymphome-CALYM, Toulouse, France; Laboratoire d'Excellence Toulouse Cancer-TOUCAN, Toulouse, France.
authors.forename: S
authors.initials: S
authors.lastname: Kheirallah
authors.forename: S
authors.initials: S
authors.lastname: Fruchon
authors.forename: L
authors.initials: L
authors.lastname: Ysebaert
authors.forename: A
authors.initials: A
authors.lastname: Blanc
authors.forename: F
authors.initials: F
authors.lastname: Capilla
authors.forename: A
authors.initials: A
authors.lastname: Marrot
authors.forename: T
authors.initials: T
authors.lastname: Alsaati
authors.forename: F X
authors.initials: FX
authors.lastname: Frenois
authors.forename: K A
authors.initials: KA
authors.lastname: Benhadji
authors.forename: J J
authors.initials: JJ
authors.lastname: Fournié
authors.forename: G
authors.initials: G
authors.lastname: Laurent
authors.forename: C
authors.initials: C
authors.lastname: Bezombes
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008224:Lymphoma, Follicular / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D051379:Mice; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034622:RNA Interference; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494819:BAD protein, human; D047428:Protein Kinase Inhibitors; D051025:bcl-Associated Death Protein; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D038362:Glycogen Synthase Kinase 3
keywords: Bad; GSK3β; apoptosis; enzastaurin; follicular lymphoma; p90RSK