Upregulation of Bfl-1/A1 in leukemia cells undergoing differentiation by all-trans retinoic acid treatment attenuates chemotherapeutic agent-induced apoptosis.
All-trans retinoic acid (ATRA) induces differentiation of NB4 and HL-60 leukemia cells, but not R4 and HL-60/Res cells. Three agents used in cancer therapy, doxorubicin (Dox), arsenic trioxide (As(2)O(3)) and paclitaxel, induce apoptosis, but not differentiation, in all of these cell lines. The induction of apoptosis by these agents is decreased in ATRA-pretreated NB4 and HL-60 cells, but not in ATRA-pretreated R4 and HL-60/Res cells. The level of Bcl-2 protein is decreased by ATRA treatment in NB4, HL-60 and HL-60/Res cells. The level of Mcl-1 protein is increased by ATRA treatment in NB4 and R4 cells, but not in HL-60 and HL-60/Res cells. Bfl-1/A1 mRNA is not expressed in these cell lines, however, its expression is markedly induced by ATRA treatment in NB4 and HL-60 cells, but not in R4 or HL-60/Res cells, which correlates with inhibition of apoptosis. Inhibiting Bfl-1/A1 mRNA upregulation in ATRA-pretreated NB4 cells using small interfering RNA (siRNA) partly recovers cell sensitivity to Dox-induced apoptosis. These data demonstrate that ATRA induction of Bfl-1/A1 in differentiated NB4 and HL-60 cells contributes to a loss of sensitivity to chemotherapy-induced apoptosis.
Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA.
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L
Xia
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Wurmbach
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S
Waxman
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Y
Jing
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D020868:Gene Silencing / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism*; D015778:Minor Histocompatibility Antigens; D010087:Oxides / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*
D000970:Antineoplastic Agents; D001152:Arsenicals; C096816:BCL2-related protein A1; D015778:Minor Histocompatibility Antigens; D010087:Oxides; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D014212:Tretinoin; D004317:Doxorubicin; D017239:Paclitaxel; D000077237:Arsenic Trioxide