RAC3 down-regulation sensitizes human chronic myeloid leukemia cells to TRAIL-induced apoptosis.
The nuclear receptor coactivator RAC3 plays important roles in many biological processes and tumorigenesis. We found that RAC3 is over-expressed in human chronic myeloid leukemia cells K562, which are normally resistant to TRAIL-induced apoptosis. RAC3 down-regulation by siRNA rendered these cells sensitive to TRAIL-induced cell death. In addition to the up-regulation of TRAIL receptors, the process involves Bid, caspases and PARP activation, loss of mitochondrial membrane potential, and release of AIF, cytochrome c and Smac/DIABLO to the cytoplasm. We conclude that RAC3 is required for TRAIL resistance and that this anti-apoptotic function is independent of its role in hormone receptor signaling.
Colo
Georgina P
GP
Laboratorio de Biología Molecular y Apoptosis, Instituto de Investigaciones Médicas Alfredo Lanari (IDIM-CONICET), Universidad de Buenos Aires, Combatiente de Malvinas 3150, C1427ARO Buenos Aires, Argentina.
Rosato
Roberto R
RR
Grant
Steven
S
Costas
Mónica A
MA
D017209:Apoptosis / Q000235:genetics; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D056921:Nuclear Receptor Coactivator 3; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D051023:BH3 Interacting Domain Death Agonist Protein; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D014157:Transcription Factors; D056921:Nuclear Receptor Coactivator 3; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases