title: Thalidomide decreases gelatinase production by malignant B lymphoid cell lines through disruption of multiple integrin-mediated signaling pathways.
abstract: BACKGROUND
  Thalidomide and its analogs are effective agents in the treatment of multiple myeloma. Since gelatinases (matrix metalloproteinases-2 and -9) play a crucial role in tumor progression, we explored the effect of thalidomide on gelatinase production by malignant B lymphoid cell lines.
  
  
  METHODS
  We investigated the effect of therapeutic doses of thalidomide on integrin-mediated production of gelatinases by malignant B lymphoid cell lines by gelatin zymography, western-blot, reverse transcriptase polymerase chain reaction and invasive capacity through Matrigel-coated Boyden chambers. We also explored the effect of thalidomide on the activation status of the main signaling pathways involved in this process.
  
  
  RESULTS
  Thalidomide strongly inhibited gelatinase production by B-cell lines and primary myeloma cells in response to fibronectin, the most efficient gelatinase inducer identified in lymphoid cells. Thalidomide disrupted integrin-mediated signaling pathways involved in gelatinase induction and release, such as Src and MAP-kinase ERK activation, resulting in decreased cell motility and invasiveness. Unexpectedly, treatment with thalidomide elicited an increase in fibronectin-induced Akt phosphorylation through phosphoinositide 3-kinase-independent pathways since thalidomide decreased fibronectin-induced phosphoinositide 3-kinase phosphorylation and reversed the inhibition of Akt phosphorylation achieved by the phosphoinositide 3-kinase inhibitors wortmannin and LY294002.
  
  
  CONCLUSIONS
  Disruption of integrin-mediated signaling may be an important mechanism through which thalidomide and its analogs impair tumor cell interactions with the microenvironment. The unexpected effects of thalidomide on Akt activation indicate the need for further studies to elucidate whether the interference with Akt downstream effects would synergize with the anti-tumor activity of thalidomide.
authors.affiliation: Department of Systemic Autoimmune Diseases, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Segarra
authors.forename: Ester
authors.initials: E
authors.lastname: Lozano
authors.forename: Marc
authors.initials: M
authors.lastname: Corbera-Bellalta
authors.forename: Carme
authors.initials: C
authors.lastname: Vilardell
authors.forename: Maria-Teresa
authors.initials: MT
authors.lastname: Cibeira
authors.forename: Jordi
authors.initials: J
authors.lastname: Esparza
authors.forename: Nora
authors.initials: N
authors.lastname: Izco
authors.forename: Joan
authors.initials: J
authors.lastname: Bladé
authors.forename: Maria C
authors.initials: MC
authors.lastname: Cid
mesh_terms: D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D018093:Gelatinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016023:Integrins / Q000378:metabolism*; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D008223:Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D013792:Thalidomide / Q000494:pharmacology*; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D016023:Integrins; D012333:RNA, Messenger; D013792:Thalidomide; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D018093:Gelatinases