Differential effects of bexarotene on intrinsic and extrinsic pathways in TRAIL-induced apoptosis in two myeloid leukemia cell lines.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces programmed cell death (apoptosis) preferentially in tumor cells. However, not all cancer cells are sensitive to TRAIL. We determined whether ligation of the retinoid receptor, RXR, would sensitize cells to TRAIL-mediated apoptosis. The leukemic cell lines KG1a (apoptosis-resistant) and ML-1 (apoptosis-sensitive) were treated with the RXR-specific retinoid bexarotene, TRAIL, or both, and apoptosis was determined. In KG1a cells, bexarotene downregulated FLIP(Long) and activated caspase-8, thereby allowing for TRAIL-triggered apoptosis. Overexpression of FLIP(Long) in ML-1 cells abrogated apoptosis. In unmodified ML-1 cells bexarotene enhanced programmed cell death via truncation of Bid and release of cytochrome C. Blockade of caspase-8 prevented enhancement in both cell lines; blockade of caspase-9 had a significant effect only in ML-1 cells. Thus, the effect of bexarotene on TRAIL-mediated programmed cell death involved proximal events of the extrinsic pathway; however, downstream signals involved the intrinsic pathway in ML-1 but not in KG1a cells. These studies add further information to the regulation of programmed cell death in leukemic cells that have to be considered when designing therapeutic strategies.
Ying
Shao Xu
SX
Shanghai Sixth Hospital, Shanghai Jiaotong University, Shanghai, China.
Seal
Sudeshna
S
Abbassi
Nissa
N
Hockenbery
David M
DM
Kiem
Hans-Peter
HP
Li
Xiao
X
Pagel
John M
JM
Gopal
Ajay K
AK
Deeg
H J
HJ
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001565:Benzoates / Q000494:pharmacology; D000077610:Bexarotene; D001713:Biphenyl Compounds / Q000494:pharmacology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D016086:Lentivirus / Q000378:metabolism; D007951:Leukemia, Myeloid / Q000188:drug therapy*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
D016588:Anticarcinogenic Agents; D001565:Benzoates; D001713:Biphenyl Compounds; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053221:TNF-Related Apoptosis-Inducing Ligand; D013764:Tetrahydronaphthalenes; C438269:diazepinylbenzoic acid; D000077610:Bexarotene; D053181:Caspase 8; D053453:Caspase 9