KMID : 0620920220540050601
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Experimental & Molecular Medicine 2022 Volume.54 No. 5 p.601 ~ p.612
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Detoxified pneumolysin derivative ¥ÄA146Ply inhibits autophagy and induces apoptosis in acute myeloid leukemia cells by activating mTOR signaling
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Zhu Tao
Zhang Hong Li Sijie Wu Kaifeng Yin Yibing Zhang Xuemei
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Abstract
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Leukemia is caused by the malignant clonal expansion of hematopoietic stem cells, and in adults, the most common type of leukemia is acute myeloid leukemia (AML). Autophagy inhibitors are often used in preclinical and clinical models in leukemia therapy. However, clinically available autophagy inhibitors and their efficacy are very limited. More effective and safer autophagy inhibitors are urgently needed for leukemia therapy. In a previous study, we showed that ¥ÄA146Ply, a mutant of pneumolysin that lacks hemolytic activity, inhibited autophagy of triple-negative breast cancer cells by activating mannose receptor (MR) and toll-like receptor 4 (TLR4) and that tumor-bearing mice tolerated ¥ÄA146Ply well. Whether this agent affects AML cells expressing TLR4 and MR and the related mechanisms remain to be determined. In this study, we found that ¥ÄA146Ply inhibited autophagy and induced apoptosis in AML cells. A mechanistic study showed that ¥ÄA146Ply inhibited autophagy by activating mammalian target of rapamycin signaling and induced apoptosis by inhibiting autophagy. ¥ÄA146Ply also inhibited autophagy and induced apoptosis in a mouse model of AML. Furthermore, the combination of ¥ÄA146Ply and chloroquine synergistically inhibited autophagy and induced apoptosis in vitro and in vivo. Overall, this study provides an alternative effective autophagy inhibitor that may be used for leukemia therapy.
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KEYWORD
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Acute myeloid leukaemia, Translational research
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