Anti-CD44 induces apoptosis in T lymphoma via mitochondrial depolarization.
A blockade of CD44 can interfere with haematopoietic and leukemic stem cell homing, the latter being considered as a therapeutic option in haematological malignancies. We here aimed to explore the molecular mechanism underlying the therapeutic efficacy of anti-CD44. We noted that in irradiated mice reconstituted with a bone marrow cell transplant, anti-CD44 exerts a stronger effect on haematopoietic reconstitution than on T lymphoma (EL4) growth. Nonetheless, in the non-reconstituted mouse anti-CD44 suffices for a prolonged survival of EL4-bearing mice, where anti-CD44-prohibited homing actively drives EL4 cells into apoptosis. In vitro, a CD44 occupancy results in a 2-4-fold increase in apoptotic EL4 cells. Death receptor expression (CD95, TRAIL, TNFRI) remains unaltered and CD95 cross-linking-mediated apoptosis is not affected. Instead, CD44 ligation promotes mitochondrial depolarization that is accompanied by caspase-9 cleavage and is inhibited in the presence of a caspase-9 inhibitor. Apoptosis becomes initiated by activation of CD44-associated phosphatase 2A (PP2A) and proceeds via ERK1/2 dephosphorylation without ERK1/2 degradation. Accordingly, CD44-induced apoptosis could be mimicked by ERK1/2 inhibition, that also promotes EL4 cell apoptosis through the mitochondrial pathway. Thus, during haematopoietic stem cell reconstitution care should be taken not to interfere by a blockade of CD44 with haematopoiesis, which could be circumvented by selectively targeting leukemic CD44 isoforms. Beyond homing/settlement in the bone marrow niche, anti-CD44 drives leukemic T cells into apoptosis via the mitochondrial death pathway by CD44 associating with PP2A. Uncovering this new pathway of CD44-induced leukemic cell death provides new options of therapeutic interference.
Rajasagi
Mohini
M
Department of Tumor Cell Biology, University Hospital of Surgery and German Cancer Research Center, Heidelberg, Germany.
von Au
Anja
A
Singh
Rahul
R
Hartmann
Natalie
N
Zöller
Margot
M
Marhaba
Rachid
R
D000818:Animals; D000912:Antibodies, Neoplasm / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D047390:Casein Kinase II / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006410:Hematopoiesis / Q000187:drug effects; D018960:Hyaluronan Receptors / Q000276:immunology*; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008223:Lymphoma / Q000201:enzymology / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology*; D013945:Thymoma / Q000201:enzymology / Q000473:pathology; D013953:Thymus Neoplasms / Q000473:pathology
D000912:Antibodies, Neoplasm; D018960:Hyaluronan Receptors; D047390:Casein Kinase II; D048049:Extracellular Signal-Regulated MAP Kinases; D054648:Protein Phosphatase 2; D053453:Caspase 9