CD26 regulates p38 mitogen-activated protein kinase-dependent phosphorylation of integrin beta1, adhesion to extracellular matrix, and tumorigenicity of T-anaplastic large cell lymphoma Karpas 299.
CD26 is an antigen with key role in T-cell biology and is expressed on selected subsets of aggressive T-cell malignancies. To elucidate the role of CD26 in tumor behavior, we examine the effect of CD26 depletion by small interfering RNA transfection of T-anaplastic large cell lymphoma Karpas 299. We show that the resultant CD26-depleted clones lose the ability to adhere to fibronectin and collagen I. Because anti-integrin beta1 blocking antibodies also prevent binding of Karpas 299 to fibronectin and collagen I, we then evaluate the CD26-integrin beta1 association. CD26 depletion does not decrease integrin beta1 expression but leads to dephosphorylation of both integrin beta1 and p38 mitogen-activated protein kinase (MAPK). Moreover, our data showing that the p38MAPK inhibitor SB203580 dephosphorylates integrin beta1 and that binding of the anti-CD26 antibody 202.36 dephosphorylates both p38MAPK and integrin beta1 on Karpas 299, leading to loss of cell adhesion to the extracellular matrix, indicate that CD26 mediates cell adhesion through p38MAPK-dependent phosphorylation of integrin beta1. Finally, in vivo experiments show that depletion of CD26 is associated with loss of tumorigenicity and greater survival. Our findings hence suggest that CD26 plays an important role in tumor development and may be a novel therapeutic target for selected neoplasms.
Sato
Tsutomu
T
Department of Lymphoma/Myeloma, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Yamochi
Tadanori
T
Yamochi
Toshiko
T
Aytac
Ugur
U
Ohnuma
Kei
K
McKee
Kathryn S
KS
Morimoto
Chikao
C
Dang
Nam H
NH
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D004317:Doxorubicin / Q000494:pharmacology; D005109:Extracellular Matrix / Q000473:pathology; D005260:Female; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology / Q000473:pathology*; D016399:Lymphoma, T-Cell / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D059005:Topoisomerase II Inhibitors; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000906:Antibodies; D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D019012:Integrin beta1; D034741:RNA, Small Interfering; D059005:Topoisomerase II Inhibitors; D004317:Doxorubicin; D048051:p38 Mitogen-Activated Protein Kinases; D018819:Dipeptidyl Peptidase 4; D004250:DNA Topoisomerases, Type II