Journal
CHEMICO-BIOLOGICAL INTERACTIONS
Volume 361, Issue -, Pages -Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.cbi.2022.109978
Keywords
Leukemia; BCL2/BCL2L1 inhibitors; p38 MAPK-mediated autophagy; Autophagic degradation of beta-TrCP mRNA; NOXA-dependent MCL1 degradation
Funding
- Ministry of Science and Technology, Taiwan [MOST110-2320-B-110-006]
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This study found that human leukemia U937 cells continuously treated with hydroquinone (HQ) showed reduced sensitivity to BCL2 and BCL2L1 inhibitors. However, the combination of WEHI-539 and ABT-199 or ABT-263 showed synergistic cytotoxicity to U937 and U937/HQ cells. Further investigation revealed that the combined treatment induced autophagy, accelerated beta-TrCP mRNA degradation, and led to NOXA-dependent MCL1 degradation.
Human leukemia U937 cells that were continuously treated with hydroquinone (HQ) were transformed into U937/HQ cells with increased MCL1 and BCL2L1 expression. Compared with their parental cells, U937/HQ cells were less sensitive to ABT-263 (BCL2/BCL2L1 inhibitor)/ABT-199 (BCL2 inhibitor) cytotoxicity. The combination of WEHI-539 (BCL2L1 inhibitor) with either ABT-199 or ABT-263 showed synergistic cytotoxicity to U937 and U937/HQ cells. Therefore, we further investigated the cytotoxic mechanism induced by the combination of WEHI-539 and ABT-199. The combined treatment of WEHI-539 and ABT-199 induced NOX4/ROS/p38 MAPK axis-mediated autophagy, which in turn accelerated beta-TrCP mRNA turnover. Downregulation of beta-TrCP increased Sp1 expression, thereby promoting Sp1-mediated NOXA transcription, which in turn induced NOXA-dependent MCL1 degradation. Enforced expression of MCL1 alleviated the cytotoxicity of WEHI-539 plus ABT-199 to induce the loss of mitochondrial membrane potential and cell viability. WEHI-539 alone induced Sp1/NOXA axis mediated MCL1 downregulation, while ABT-199 significantly decreased the dose of WEHI-539 by approximately 350-and 50-fold to induce MCL1 suppression in parental and HQ-selected cells, respectively. Furthermore, WEHI-539 sensitized ABT-199-resistant U937 cells to ABT-199 cytotoxicity by inducing NOXA-mediated degradation of MCL1. Collectively, the data in this study indicate that ABT-199 and WEHI-539 cooperatively induce NOXA-dependent MCL1 degradation, and the inhibition of MCL1 mainly explains their combined cytotoxicity in parental, HQ-selected, and ABT-199-resistant U937 cells.
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