A20 inhibits doxorubicin-induced macrophage maturation and apoptosis through mTOR signaling in classical Hodgkin lymphoma

Articles in Press

Document Type : Original Article

Authors

1 Faculty of Biotechnology, Vietnam National University of Agriculture, Hanoi, Vietnam

2 Military Hospital 103, Vietnam Military Medical University, Phung Hung, Ha Dong, Hanoi, Vietnam

3 Department of Pathophysiology, Vietnam Military Medical University, Phung Hung, Ha Dong, Hanoi, Vietnam

4 Institute of Biology, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi, Vietnam

5 Publishing House for Science Technology, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, HaNoi, VietNam

6 Department of Military Epidemiology, Vietnam Military Medical University, Phung Hung, Ha Dong, Hanoi, Vietnam

7 108 Military Central Hospital, Tran Hung Dao, Hai Ba Trung, Hanoi, Vietnam

10.22038/ijbms.2025.86862.18767

Abstract

Objective(s): Classical Hodgkin lymphoma (cHL) is identified by the appearance of Hodgkin and Reed-Sternberg cells. A20 and CYLD are deubiquitinating enzymes involved in negatively regulating NF-κB-mediated immune response. Vincristine (Vinc) and doxorubicin (Dox) are classical antitumor drugs, in which Dox serves a key role in chemotherapy against cHL and Vinc induces disruption of microtubule function that inhibits mitosis of cancer cells. Little is known about the roles of A20/CYLD in regulating macrophage function from cHL patients upon treatment with Vinc or Dox. This study, therefore, asked whether A20/CYLD expression affects function of macrophages in cHL cases. 
Materials and Methods: Macrophages from cHL patients differentiated from bone marrow cells were exposed to Vinc or Dox. Gene expression levels were determined by real time-qPCR, cell maturation, apoptosis and phagocytosis by flow cytometry, and cytokine release by ELISA. 
Results: Dox induced maturation, apoptosis, and phagocytosis of macrophages in cHL cases. Moreover, the percentage of CD68+CD40+, but not CD68+CD86+ cells as well as levels of IL-1β were further enhanced when exposed to A20 siRNA, whereas the absence of CYLD unaltered macrophage function in cHL patients. Importantly, the increased numbers of A20-sensitive CD68+CD40+ and Annexin V-PI+ cells as well as enhanced levels of caspase 3 were abolished in the presence of mTOR inhibitor Everolimus. 
Conclusion: The present study indicates that Dox-induced macrophage maturation and apoptosis are dependent on A20 expression through mTOR signaling. Moreover, inhibition of Dox-induced macrophage maturation in the patients with low A20 expression by Everolimus might represent a promising therapy for A20-sensitive cHL cases.

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References

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Iranian Journal of Basic Medical Sciences

Articles in Press, Accepted Manuscript
Available Online from 07 July 2025

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