Differential effects of chemotherapeutic drugs versus the MDM-2 antagonist Nutlin-3 on cell cycle progression and induction of apoptosis in SKW6.4 lymphoblastoid B-cells

被引:7
作者
Barbarotto, Elisa [2 ]
Corallini, Federica [3 ]
Rimondi, Erika [2 ]
Fadda, Roberto [2 ]
Mischiati, Carlo [2 ]
Gril, Vittorio [3 ]
Vaccarezza, Mauro [1 ]
Celeghini, Claudio [3 ]
机构
[1] Univ Cassino, Dept Hlth & Motor Sci, I-03043 Cassino, Italy
[2] Univ Ferrara, Dept Morphol & Embryol, I-44100 Ferrara, Italy
[3] Univ Trieste, Dept Biomed, I-34138 Trieste, Italy
关键词
TRAIL; p53; chemotherapeutic drugs; cell cycle;
D O I
10.1002/jcb.21649
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We have compared the cytotoxic/cytostatic responses of the SKW6.4 lymphoblastoid B-cells to the alkylating agent chlorambucil, the purine analog fludarabine, the non-genotoxic activator of the p53 pathway, Nutlin-3, used alone or in association with the death-inducing ligand recombinant TRAIL. Exposure to chlorambucil, fludarabine, and Nutlin-3 induced p53 accumulation and variably affected cell cycle progression in SKW6.4 lymphoblastoid cells. In particular, chlorambucil induced cell cycle accumulation at the G2/M checkpoint; Nutlin-3 induced early cell cycle arrest at the G1/S checkpoint, while fludarabine showed an intermediate behavior. On the other hand, recombinant TRAIL alone did not affect cell cycle progression but induced a rapid increase of apoptosis. Analysis of the gene expression profile of the p53-transcriptional targets showed distinct features between chlorambucil, Nutlin-3 and fludarabine, which likely account for their differential effect on cell cycle in SKW6.4 cells. In particular, chlorambucil upregulated the steady-state mRNA expression of SFN/14-3-3 sigma, a gene involved in G2/M cell cycle arrest. Of note, all agonists upregulated TRAIL-R2 expression in SKW6.4 cells both at the mRNA and protein levels. Consistently, pretreatment with chlorambucil, fludarabine and Nutlin-3 enhanced SKW6.4 sensitivity to TRAIL-mediated apoptosis.
引用
收藏
页码:595 / 605
页数:11
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