Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Apr 26, 2024; 16(4): 444-458
Published online Apr 26, 2024. doi: 10.4252/wjsc.v16.i4.444
Gossypol acetic acid regulates leukemia stem cells by degrading LRPPRC via inhibiting IL-6/JAK1/STAT3 signaling or resulting mitochondrial dysfunction
Cheng-Jin Ai, Ling-Juan Chen, Li-Xuan Guo, Ya-Ping Wang, Zi-Yi Zhao
Cheng-Jin Ai, Ling-Juan Chen, Li-Xuan Guo, Department of Laboratory Medicine, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 641000, Sichuan Province, China
Ya-Ping Wang, Department of Ophthalmology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 641000, Sichuan Province, China
Zi-Yi Zhao, Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 641000, Sichuan Province, China
Zi-Yi Zhao, Traditional Chinese Medicine Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Chengdu University of Traditional Chinese Medicine, Chengdu 641000, Sichuan Province, China
Co-first authors: Cheng-Jin Ai and Ling-Juan Chen.
Author contributions: Ai CJ and Zhao ZY designed the experiments and wrote manuscript; Ai CJ, Chen LJ, Guo LX, and Wang YP performed molecular-related experiments in this study; Ai CJ and Chen LJ performed experiments on processing cells, and they are co-first authors of this manuscript; Zhao ZY is responsible for data collection and performed statistical analysis and revised manuscript; and all authors read and approved the final manuscript.
Institutional review board statement: No human or animal subjects was involved in this study.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: All data generated or analyzed during this study are included in this published article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Zi-Yi Zhao, PhD, Professor, Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, Shi-er-qiao Road, Chengdu 641000, Sichuan Province, China. zhaoziyi@cdutcm.edu.cn
Received: January 15, 2024
Peer-review started: January 15, 2024
First decision: January 29, 2024
Revised: February 11, 2024
Accepted: March 14, 2024
Article in press: March 14, 2024
Published online: April 26, 2024
Processing time: 100 Days and 13.2 Hours
Abstract
BACKGROUND

Leukemia stem cells (LSCs) are found to be one of the main factors contributing to poor therapeutic effects in acute myeloid leukemia (AML), as they are protected by the bone marrow microenvironment (BMM) against conventional therapies. Gossypol acetic acid (GAA), which is extracted from the seeds of cotton plants, exerts anti-tumor roles in several types of cancer and has been reported to induce apoptosis of LSCs by inhibiting Bcl2.

AIM

To investigate the exact roles of GAA in regulating LSCs under different microenvironments and the exact mechanism.

METHODS

In this study, LSCs were magnetically sorted from AML cell lines and the CD34+CD38- population was obtained. The expression of leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) and forkhead box M1 (FOXM1) was evaluated in LSCs, and the effects of GAA on malignancies and mitochondrial function were measured.

RESULTS

LRPPRC was found to be upregulated, and GAA inhibited cell proliferation by degrading LRPPRC. GAA induced LRPPRC degradation and inhibited the activation of interleukin 6 (IL-6)/janus kinase (JAK) 1/signal transducer and activator of transcription (STAT) 3 signaling, enhancing chemosensitivity in LSCs against conventional chemotherapies, including L-Asparaginase, Dexamethasone, and cytarabine. GAA was also found to downregulate FOXM1 indirectly by regulating LRPPRC. Furthermore, GAA induced reactive oxygen species accumulation, disturbed mitochondrial homeostasis, and caused mitochondrial dysfunction. By inhibiting IL-6/JAK1/STAT3 signaling via degrading LRPPRC, GAA resulted in the elimination of LSCs. Meanwhile, GAA induced oxidative stress and subsequent cell damage by causing mitochondrial damage.

CONCLUSION

Taken together, the results indicate that GAA might overcome the BMM protective effect and be considered as a novel and effective combination therapy for AML.

Keywords: Leukemia stem cells; Gossypol acetic acid; Reactive oxygen species; Mitochondrial dysfunction; Interleukin 6/janus kinase 1/signal transducer and activator of transcription 3 signaling

Core Tip: Gossypol acetic acid (GAA) inhibited janus kinase 1/signal transducer and activator of transcription 3 signaling activated by interleukin 6 in leukemia stem cells (LSCs). GAA sensitizes to chemoagent, including cytarabine, Dexamethasone and L-Asparaginase in LSCs. GAA decreased leucine-rich pentatricopeptide repeat-containing protein and subsequent downregulated forkhead box M1, which are critical and necessary for stemness of LSCs. GAA induces mitochondrial dysfunction via inducing reactive oxygen species accumulation. GAA might eliminate the effects of inflammatory environment on LSCs.