title: Sorafenib inhibits cell migration and stroma-mediated bortezomib resistance by interfering B-cell receptor signaling and protein translation in mantle cell lymphoma.
abstract: OBJECTIVE
  We evaluated the antitumoral properties of the multikinase inhibitor sorafenib in mantle cell lymphoma (MCL), an aggressive B lymphoma for which current therapies have shown limited efficacy.
  
  
  METHODS
  Sensitivity to sorafenib was analyzed in MCL cell lines and primary samples in the context of BCR and microenvironment simulation. Sorafenib signaling was characterized by quantitative PCR, Western blotting, immunofluorescence, and protein immunoprecipitation. Migration analysis included flow cytometric counting, actin polymerization assays, and siRNA-mediated knockdown of focal adhesion kinase (FAK). In vivo antitumor effect of sorafenib and bortezomib was analyzed in an MCL xenograft mouse model.
  
  
  RESULTS
  Sorafenib rapidly dephosphorylates the BCR-associated kinases, Syk and Lyn, as well as FAK, an Src target involved in focal adhesion. In this line, sorafenib displays strong synergy with the Syk inhibitor, R406. Sorafenib also blocks Mcl-1 and cyclin D1 translation, which promotes an imbalance between pro- and antiapoptotic proteins and facilitates Bax release from cyclin D1, leading to the induction of mitochondrial apoptosis and caspase-dependent and -independent mechanisms. Moreover, sorafenib inhibits MCL cell migration and CXCL12-induced actin polymerization. FAK knockdown partially prevents this inhibitory effect, indicating that FAK is a relevant target of sorafenib. Furthermore, sorafenib enhances the antitumoral activity of bortezomib in an MCL xenograft mouse model as well as overcomes stroma-mediated bortezomib resistance in MCL cells.
  
  
  CONCLUSIONS
  We show for the first time that sorafenib interferes with BCR signaling, protein translation and modulates the microenvironment prosurvival signals in MCL, suggesting that sorafenib, alone or in combination with bortezomib, may represent a promising approach to treat patients with MCL.
authors.affiliation: Hematopathology Unit, Department of Pathology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Xargay-Torrent
authors.forename: Mónica
authors.initials: M
authors.lastname: López-Guerra
authors.forename: Arnau
authors.initials: A
authors.lastname: Montraveta
authors.forename: Ifigènia
authors.initials: I
authors.lastname: Saborit-Villarroya
authors.forename: Laia
authors.initials: L
authors.lastname: Rosich
authors.forename: Alba
authors.initials: A
authors.lastname: Navarro
authors.forename: Patricia
authors.initials: P
authors.lastname: Pérez-Galán
authors.forename: Gaël
authors.initials: G
authors.lastname: Roué
authors.forename: Elias
authors.initials: E
authors.lastname: Campo
authors.forename: Dolors
authors.initials: D
authors.lastname: Colomer
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D054377:Chemokine CXCL12 / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D014176:Protein Biosynthesis / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D055503:Protein Multimerization; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D000077157:Sorafenib; D017154:Stromal Cells; D014183:Transplantation, Heterologous
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; D054377:Chemokine CXCL12; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011947:Receptors, Antigen, B-Cell; D019938:Cyclin D1; D009536:Niacinamide; D000077157:Sorafenib; D020169:Caspases