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

1
Laboratory of Immunobiology, School of Life Sciences, BK21 FOUR KNU Creative BioResearch Group, Kyungpook National University, Daegu 41566, Korea
2
Astrogen Inc., Techno-Building 313, Kyungpook National University, Daegu 41566, Korea
3
Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu 41566, Korea
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(12), 3845; https://doi.org/10.3390/cancers12123845
Received: 13 November 2020 / Revised: 11 December 2020 / Accepted: 16 December 2020 / Published: 19 December 2020
(This article belongs to the Section Cancer Therapy)
Chemotherapy resistance in human T-cell acute lymphoblastic leukemia (T-ALL), an aggressive neoplasm, results in poor prognosis despite advances in treatment modalities. Toward the identification of an effective alternative, in the present study, we elucidated the mechanism underlying the antitumor activity of the CDK7 inhibitor BS-181 using malignant cells (Jurkat A3, U937, and HeLa) and normal human peripheral T cells. This is the first report to demonstrate that BS-181 antitumor activity is mainly caused by extrinsic apoptosis induction through cell-surface TRAIL/DR5 levels in human T-ALL Jurkat T cells. Moreover, combined treatment with recombinant TRAIL (rTRAIL) exerted synergistic effects on BS-181 cytotoxicity against malignant cells but not normal human peripheral T cells by augmenting both the extrinsic and intrinsic BCL-2-sensitive apoptosis pathways. Our findings suggest that the combination with rTRAIL may facilitate BS-181 antitumor activity against T-ALL cells while minimizing associated side effects, therefore potentially being applicable to clinical human T-ALL treatment.
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, ΔΨm 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/ΔΨm 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. View Full-Text
Keywords: CDK inhibitor; G1 arrest; extrinsic apoptotic pathway; TRAIL; DR5; leukemia CDK inhibitor; G1 arrest; extrinsic apoptotic pathway; TRAIL; DR5; leukemia
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MDPI and ACS Style

Park, S.Y.; Kim, K.Y.; Jun, D.Y.; Hwang, S.-K.; Kim, Y.H. G1 Cell Cycle Arrest and Extrinsic Apoptotic Mechanisms Underlying the Anti-Leukemic Activity of CDK7 Inhibitor BS-181. Cancers 2020, 12, 3845. https://doi.org/10.3390/cancers12123845

AMA Style

Park SY, Kim KY, Jun DY, Hwang S-K, Kim YH. G1 Cell Cycle Arrest and Extrinsic Apoptotic Mechanisms Underlying the Anti-Leukemic Activity of CDK7 Inhibitor BS-181. Cancers. 2020; 12(12):3845. https://doi.org/10.3390/cancers12123845

Chicago/Turabian Style

Park, Shin Y., Ki Y. Kim, Do Y. Jun, Su-Kyeong Hwang, and Young H. Kim 2020. "G1 Cell Cycle Arrest and Extrinsic Apoptotic Mechanisms Underlying the Anti-Leukemic Activity of CDK7 Inhibitor BS-181" Cancers 12, no. 12: 3845. https://doi.org/10.3390/cancers12123845

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