G1 Cell Cycle Arrest and Extrinsic Apoptotic Mechanisms Underlying the Anti-Leukemic Activity of CDK7 Inhibitor BS-181

Cancers

Su-Kyeong Hwang¹  DoYoun Jun¹  KiYun Kim²  YoungHo Kim²  ShinYoung Park² 

[1] Astrogen Inc., Techno-Building 313, Kyungpook National University, Daegu 41566, Korea;Laboratory of Immunobiology, School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Korea;

关键词: CDK inhibitor;    G₁ arrest;    extrinsic apoptotic pathway;    TRAIL;    DR5;    leukemia;   

DOI  :  10.3390/cancers12123845

来源: DOAJ

【 摘 要 】

In vitro antitumor activity of the CDK7 inhibitor BS-181 against human T-ALL Jurkat cells was determined. Treatment of Jurkat clones (JT/Neo) with BS-181 caused cytotoxicity and several apoptotic events, including TRAIL/DR4/DR5 upregulation, c-FLIP down-regulation, BID cleavage, BAK activation, ΔΨ_m loss, caspase-8/9/3 activation, and PARP cleavage. However, the BCL-2-overexpressing Jurkat clone (JT/BCL-2) abrogated these apoptotic responses. CDK7 catalyzed the activating phosphorylation of CDK1 (Thr161) and CDK2 (Thr160), and CDK-directed retinoblastoma phosphorylation was attenuated in both BS-181-treated Jurkat clones, whereas only JT/BCL-2 cells exhibited G₁ cell cycle arrest. The G₁-blocker hydroxyurea augmented BS-181-induced apoptosis by enhancing TRAIL/DR4/DR5 upregulation and c-FLIP down-regulation. BS-181-induced FITC–annexin V-positive apoptotic cells were mostly in the sub-G₁ and G₁ phases. BS-181-induced cytotoxicity and mitochondrial apoptotic events (BAK activation/ΔΨ_m loss/caspase-9 activation) in Jurkat clones I2.1 (FADD-deficient) and I9.2 (caspase-8-deficient) were significantly lower than in A3 (wild-type). Exogenously added recombinant TRAIL (rTRAIL) markedly synergized BS-181-induced apoptosis in A3 cells but not in normal peripheral T cells. The cotreatment cytotoxicity was significantly reduced by the DR5-blocking antibody but not by the DR4-blocking antibody. These results demonstrated that the BS-181 anti-leukemic activity is attributed to extrinsic TRAIL/DR5-dependent apoptosis preferentially induced in G₁-arrested cells, and that BS-181 and rTRAIL in combination may hold promise for T-ALL treatment.

【 授权许可】

Unknown