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Overcoming adaptive resistance in AML by synergistically targeting FOXO3A-GNG7-mTOR axis with FOXO3A inhibitor Gardenoside and rapamycin
Therapeutic targeting FOXO3A (a forkhead transcription factor) represents a promising strategy to suppress acute myeloid leukemia (AML). However, the effective inhibitors that target FOXO3A are lacking and the adaptive response signaling weakens the cytotoxic effect of FOXO3A depletion on AML cells....
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Chongqing Medical University
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10425752/ https://www.ncbi.nlm.nih.gov/pubmed/37588187 http://dx.doi.org/10.1016/j.gendis.2023.01.002 |
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author | Chen, Zhe Guo, Qian Huang, Shichen Li, Lei Wu, Feng Liu, Zhilong Li, Zhigang Chen, Tao Song, Guanbin Xu, Shuangnian Chen, Jieping Hou, Yu |
author_facet | Chen, Zhe Guo, Qian Huang, Shichen Li, Lei Wu, Feng Liu, Zhilong Li, Zhigang Chen, Tao Song, Guanbin Xu, Shuangnian Chen, Jieping Hou, Yu |
author_sort | Chen, Zhe |
collection | PubMed |
description | Therapeutic targeting FOXO3A (a forkhead transcription factor) represents a promising strategy to suppress acute myeloid leukemia (AML). However, the effective inhibitors that target FOXO3A are lacking and the adaptive response signaling weakens the cytotoxic effect of FOXO3A depletion on AML cells. Here, we show that FOXO3A deficiency induces a compensatory response involved in the reactive activation of mTOR that leads to signaling rebound and adaptive resistance. Mitochondrial metabolism acts downstream of mTOR to provoke activation of JNK/c-JUN via reactive oxygen species (ROS). At the molecular level, FOXO3A directly binds to the promoter of G protein gamma subunit 7 (GNG7) and preserves its expression, while GNG7 interacts with mTOR and restricts phosphorylated activation of mTOR. Consequently, combinatorial inhibition of FOXO3A and mTOR show a synergistic cytotoxic effect on AML cells and prolongs survival in a mouse model of AML. Through a structure-based virtual screening, we report one potent small-molecule FOXO3A inhibitor (Gardenoside) that exhibits a strong effect of anti-FOXO3A DNA binding. Gardenoside synergizes with rapamycin to substantially reduce tumor burden and extend survival in AML patient-derived xenograft model. These results demonstrate that mTOR can mediate adaptive resistance to FOXO3A inhibition and validate a combinatorial approach for treating AML. |
format | Online Article Text |
id | pubmed-10425752 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Chongqing Medical University |
record_format | MEDLINE/PubMed |
spelling | pubmed-104257522023-08-16 Overcoming adaptive resistance in AML by synergistically targeting FOXO3A-GNG7-mTOR axis with FOXO3A inhibitor Gardenoside and rapamycin Chen, Zhe Guo, Qian Huang, Shichen Li, Lei Wu, Feng Liu, Zhilong Li, Zhigang Chen, Tao Song, Guanbin Xu, Shuangnian Chen, Jieping Hou, Yu Genes Dis Full Length Article Therapeutic targeting FOXO3A (a forkhead transcription factor) represents a promising strategy to suppress acute myeloid leukemia (AML). However, the effective inhibitors that target FOXO3A are lacking and the adaptive response signaling weakens the cytotoxic effect of FOXO3A depletion on AML cells. Here, we show that FOXO3A deficiency induces a compensatory response involved in the reactive activation of mTOR that leads to signaling rebound and adaptive resistance. Mitochondrial metabolism acts downstream of mTOR to provoke activation of JNK/c-JUN via reactive oxygen species (ROS). At the molecular level, FOXO3A directly binds to the promoter of G protein gamma subunit 7 (GNG7) and preserves its expression, while GNG7 interacts with mTOR and restricts phosphorylated activation of mTOR. Consequently, combinatorial inhibition of FOXO3A and mTOR show a synergistic cytotoxic effect on AML cells and prolongs survival in a mouse model of AML. Through a structure-based virtual screening, we report one potent small-molecule FOXO3A inhibitor (Gardenoside) that exhibits a strong effect of anti-FOXO3A DNA binding. Gardenoside synergizes with rapamycin to substantially reduce tumor burden and extend survival in AML patient-derived xenograft model. These results demonstrate that mTOR can mediate adaptive resistance to FOXO3A inhibition and validate a combinatorial approach for treating AML. Chongqing Medical University 2023-01-25 /pmc/articles/PMC10425752/ /pubmed/37588187 http://dx.doi.org/10.1016/j.gendis.2023.01.002 Text en © 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Full Length Article Chen, Zhe Guo, Qian Huang, Shichen Li, Lei Wu, Feng Liu, Zhilong Li, Zhigang Chen, Tao Song, Guanbin Xu, Shuangnian Chen, Jieping Hou, Yu Overcoming adaptive resistance in AML by synergistically targeting FOXO3A-GNG7-mTOR axis with FOXO3A inhibitor Gardenoside and rapamycin |
title | Overcoming adaptive resistance in AML by synergistically targeting FOXO3A-GNG7-mTOR axis with FOXO3A inhibitor Gardenoside and rapamycin |
title_full | Overcoming adaptive resistance in AML by synergistically targeting FOXO3A-GNG7-mTOR axis with FOXO3A inhibitor Gardenoside and rapamycin |
title_fullStr | Overcoming adaptive resistance in AML by synergistically targeting FOXO3A-GNG7-mTOR axis with FOXO3A inhibitor Gardenoside and rapamycin |
title_full_unstemmed | Overcoming adaptive resistance in AML by synergistically targeting FOXO3A-GNG7-mTOR axis with FOXO3A inhibitor Gardenoside and rapamycin |
title_short | Overcoming adaptive resistance in AML by synergistically targeting FOXO3A-GNG7-mTOR axis with FOXO3A inhibitor Gardenoside and rapamycin |
title_sort | overcoming adaptive resistance in aml by synergistically targeting foxo3a-gng7-mtor axis with foxo3a inhibitor gardenoside and rapamycin |
topic | Full Length Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10425752/ https://www.ncbi.nlm.nih.gov/pubmed/37588187 http://dx.doi.org/10.1016/j.gendis.2023.01.002 |
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