Research Alert
BACKGROUND
Newswise — 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.
Key Words: 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.
- Citation: Ai CJ, Chen LJ, Guo LX, Wang YP, Zhao ZY. Gossypol acetic acid regulates leukemia stem cells by degrading LRPPRC via inhibiting IL-6/JAK1/STAT3 signaling or resulting mitochondrial dysfunction. World J Stem Cells 2024; 16(4): 444-458
- URL: https://www.wjgnet.com/1948-0210/full/v16/i4/444.htm
- DOI: https://dx.doi.org/10.4252/wjsc.v16.i4.444
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