Celecoxib disrupts the canonical apoptotic network in HTLV-I cells through activation of Bax and inhibition of PKB/Akt.
Adult T-cell leukemia/lymphoma (ATLL) is an aggressive lymphoproliferative disease of very poor clinical prognosis associated with infection by the human T-cell leukemia virus type I (HTLV-I). Treatment of patients with ATLL using conventional chemotherapy has limited benefit because HTLV-I cells are refractory to most apoptosis-inducing agents. In this study, we report that Celecoxib induces cell death via the intrinsic mitochondrial pathway in HTLV-I transformed leukemia cells. Treatment with Celecoxib was associated with activation of Bax, decreased expression of Mcl-1, loss of the mitochondrial membrane potential and caspase-9-dependent apoptosis. These effects were independent from Bcl-2 and Bcl-xL. We also found that Celecoxib inhibited the Akt/GSK3 beta survival pathway in HTLV-I cells.
Sinha-Datta
Uma
U
Department of Microbiology, Immunology, and Molecular Genetics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA.
Taylor
John M
JM
Brown
Megan
M
Nicot
Christophe
C
D017209:Apoptosis / Q000187:drug effects*; D000068579:Celecoxib; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000378:metabolism / Q000473:pathology*; D008928:Mitochondria / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism
C494811:BCL2L1 protein, human; D016861:Cyclooxygenase Inhibitors; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011720:Pyrazoles; D013449:Sulfonamides; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D051057:Proto-Oncogene Proteins c-akt; D000068579:Celecoxib