AI Chat Paper
Note: Please note that the following content is generated by AMiner AI. SciOpen does not take any responsibility related to this content.
{{lang === 'zh_CN' ? '文章概述' : 'Summary'}}
{{lang === 'en_US' ? '中' : 'Eng'}}
Chat more with AI
Powered by AMiner. Clicking this button will take you away from SciOpen.
Home Genes & Diseases Article
PDF (5.3 MB)
Cite
EndNote(RIS) BibTeX
Collect
Submit Manuscript AI Chat Paper
Show Outline
Outline
Show full outline
Hide outline
Outline
Show full outline
Hide outline
Full Length Article | Open Access

Overcoming adaptive resistance in AML by synergistically targeting FOXO3A-GNG7-mTOR axis with FOXO3A inhibitor Gardenoside and rapamycin

Zhe Chena,b,1, Qian Guoc,1, Shichen Huangd, Lei Lia, Feng Wub, Zhilong Liua, Zhigang Lib, Tao Chena, Guanbin Songc, Shuangnian Xua( ), Jieping Chena( ), Yu Houb,#( )
Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China
Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
Chongqing Foreign Language School, Chongqing 400039, China

Peer review under responsibility of Chongqing Medical University.

1 These authors contributed equally.

# Lead contact.

Show Author Information

Abstract

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.

Keywords

AMLCombinatorial inhibitionFOXO3AGNG7mTOR

References

1

Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209-2221.
Crossref Google Scholar
2

Yamashita M, Dellorusso PV, Olson OC, et al. Dysregulated haematopoietic stem cell behaviour in myeloid leukaemogenesis. Nat Rev Cancer. 2020;20(7):365-382.
Crossref Google Scholar
3

Bowman RL, Busque L, Levine RL. Clonal hematopoiesis and evolution to hematopoietic malignancies. Cell Stem Cell. 2018;22(2):157-170.
Crossref Google Scholar
4

Carter JL, Hege K, Yang J, et al. Targeting multiple signaling pathways: the new approach to acute myeloid leukemia therapy. Signal Transduct Targeted Ther. 2020;5(1):288.
Crossref Google Scholar
5

Golson ML, Kaestner KH. Fox transcription factors: from development to disease. Development. 2016;143(24):4558-4570.
Crossref Google Scholar
6

Hannenhalli S, Kaestner KH. The evolution of Fox genes and their role in development and disease. Nat Rev Genet. 2009;10(4):233-240.
Crossref Google Scholar
7

Liu Y, Ao X, Ding W, et al. Critical role of FOXO3a in carcinogenesis. Mol Cancer. 2018;17(1):104.
Crossref Google Scholar
8

Warr MR, Binnewies M, Flach J, et al. FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature. 2013;494(7437):323-327.
Crossref Google Scholar
9

Sykes SM, Lane SW, Bullinger L, et al. AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias. Cell. 2011;146(5):697-708.
Crossref Google Scholar
10

Santamaría CM, Chillón MC, García-Sanz R, et al. High FOXO3a expression is associated with a poorer prognosis in AML with normal cytogenetics. Leuk Res. 2009;33(12):1706-1709.
Crossref Google Scholar
11

Kornblau SM, Singh N, Qiu Y, et al. Highly phosphorylated FOXO3A is an adverse prognostic factor in acute myeloid leukemia. Clin Cancer Res. 2010;16(6):1865-1874.
Crossref Google Scholar
12

Santos MA, Faryabi RB, Ergen AV, et al. DNA-damage-induced differentiation of leukaemic cells as an anti-cancer barrier. Nature. 2014;514(7520):107-111.
Crossref Google Scholar
13

Jaaks P, Coker EA, Vis DJ, et al. Effective drug combinations in breast, colon and pancreatic cancer cells. Nature. 2022;603(7899):166-173.
Crossref Google Scholar
14

Bertram K, Leary PJ, Boudesco C, et al. Inhibitors of Bcl-2 and Bruton's tyrosine kinase synergize to abrogate diffuse large B-cell lymphoma growth in vitro and in orthotopic xenotransplantation models. Leukemia. 2022;36(4):1035-1047.
Crossref Google Scholar
15

Wilson WH, Wright GW, Huang DW, et al. Effect of ibrutinib with R-CHOP chemotherapy in genetic subtypes of DLBCL. Cancer Cell. 2021;39(12):1643-1653.
Crossref Google Scholar
16

He Y, Sun L, Xu Y, et al. Combined inhibition of PI3Kδ and FLT3 signaling exerts synergistic antitumor activity and overcomes acquired drug resistance in FLT3-activated acute myeloid leukemia. Cancer Lett. 2018;420:49-59.
Crossref Google Scholar
17

Bruner JK, Ma HS, Li L, et al. Adaptation to TKI treatment reactivates ERK signaling in tyrosine kinase-driven leukemias and other malignancies. Cancer Res. 2017;77(20):5554-5563.
Crossref Google Scholar
18

Jiang X, Mak PY, Mu H, et al. Disruption of Wnt/β-catenin exerts antileukemia activity and synergizes with FLT3 inhibition in FLT3-mutant acute myeloid leukemia. Clin Cancer Res. 2018;24(10):2417-2429.
Crossref Google Scholar
19

Wang J, Li Y, Wang P, et al. Leukemogenic chromatin alterations promote AML leukemia stem cells via a KDM4C-ALKBH5-AXL signaling axis. Cell Stem Cell. 2020;27(1):81-97.e8.
Crossref Google Scholar
20

Chen Z, Li L, Wu W, et al. Exercise protects proliferative muscle satellite cells against exhaustion via the Igfbp7-Akt-mTOR axis. Theranostics. 2020;10(14):6448-6466.
Crossref Google Scholar
21

Chen Z, Huo D, Li L, et al. Nuclear DEK preserves hematopoietic stem cells potential via NCoR1/HDAC3-Akt1/2-mTOR axis. J Exp Med. 2021;218(5):e20201974.
Crossref Google Scholar
22

Baell JB, Holloway GA. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. J Med Chem. 2010;53(7):2719-2740.
Crossref Google Scholar
23

Friesner RA, Banks JL, Murphy RB, et al. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J Med Chem. 2004;47(7):1739-1749.
Crossref Google Scholar
24

van Galen P, Hovestadt V, Wadsworth II MH, et al. Single-cell RNA-seq reveals AML hierarchies relevant to disease progression and immunity. Cell. 2019;176(6):1265-1281.
Crossref Google Scholar
25

Li D, Li T, Shang Z, et al. Combined inhibition of Notch and FLT3 produces synergistic cytotoxic effects in FLT3/ITD+ acute myeloid leukemia. Signal Transduct Targeted Ther. 2020;5(1):21.
Crossref Google Scholar
26

Wang Y, Jin W, Jia X, et al. Transcriptional repression of CDKN2D by PML/RARα contributes to the altered proliferation and differentiation block of acute promyelocytic leukemia cells. Cell Death Dis. 2014;5(10):e1431.
Crossref Google Scholar
27

Bertacchini J, Heidari N, Mediani L, et al. Targeting PI3K/AKT/mTOR network for treatment of leukemia. Cell Mol Life Sci. 2015;72(12):2337-2347.
Crossref Google Scholar
28

Beauchamp EM, Abedin SM, Radecki SG, et al. Identification and targeting of novel CDK9 complexes in acute myeloid leukemia. Blood. 2019;133(11):1171-1185.
Crossref Google Scholar
29

Lin X, Fang Q, Chen S, et al. Heme oxygenase-1 suppresses the apoptosis of acute myeloid leukemia cells via the JNK/c-JUN signaling pathway. Leuk Res. 2015;39(5):544-552.
Crossref Google Scholar
30

Zhang D, Zhou Q, Huang D, et al. ROS/JNK/c-Jun axis is involved in oridonin-induced caspase-dependent apoptosis in human colorectal cancer cells. Biochem Biophys Res Commun. 2019;513(3):594-601.
Crossref Google Scholar
31

Wu JR, You RI, Hu CT, et al. Hydrogen peroxide inducible clone-5 sustains NADPH oxidase-dependent reactive oxygen species-c-Jun N-terminal kinase signaling in hepatocellular carcinoma. Oncogenesis. 2019;8(8):40.
Crossref Google Scholar
32

Yilmaz OH, Valdez R, Theisen BK, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature. 2006;441(7092):475-482.
Crossref Google Scholar
33

Bennett BL, Sasaki DT, Murray BW, et al. SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci U S A. 2001;98(24):13681-13686.
Crossref Google Scholar
34

Khatri S, Yepiskoposyan H, Gallo CA, et al. FOXO3a regulates glycolysis via transcriptional control of tumor suppressor TSC1. J Biol Chem. 2010;285(21):15960-15965.
Crossref Google Scholar
35

Chen CC, Jeon SM, Bhaskar PT, et al. FoxOs inhibit mTORC1 and activate Akt by inducing the expression of Sestrin3 and Rictor. Dev Cell. 2010;18(4):592-604.
Crossref Google Scholar
36

Melick CH, Jewell JL. Regulation of mTORC1 by upstream stimuli. Genes. 2020;11(9):989.
Crossref Google Scholar
37

Hartmann S, Szaumkessel M, Salaverria I, et al. Loss of protein expression and recurrent DNA hypermethylation of the GNG7 gene in squamous cell carcinoma of the head and neck. J Appl Genet. 2012;53(2):167-174.
Crossref Google Scholar
38

Shibata K, Tanaka S, Shiraishi T, et al. G-protein gamma 7 is down-regulated in cancers and associated with p 27kip1-induced growth arrest. Cancer Res. 1999;59(5):1096-1101.
Google Scholar
39

Duc NM, Kim HR, Chung KY. Structural mechanism of G protein activation by G protein-coupled receptor. Eur J Pharmacol. 2015;763(Pt B):214-222.
Crossref Google Scholar
40

Syrovatkina V, Alegre KO, Dey R, et al. Regulation, signaling, and physiological functions of G-proteins. J Mol Biol. 2016;428(19):3850-3868.
Crossref Google Scholar
41

Liu J, Ji X, Li Z, et al. G protein γ subunit 7 induces autophagy and inhibits cell division. Oncotarget. 2016;7(17):24832-24847.
Crossref Google Scholar
42

Lai WS, Ding YL. GNG7 silencing promotes the proliferation and differentiation of placental cytotrophoblasts in preeclampsia rats through activation of the mTOR signaling pathway. Int J Mol Med. 2019;43(5):1939-1950.
Crossref Google Scholar
43

Lai W, Yu L. Elevated microRNA 183 impairs trophoblast migration and invasiveness by downregulating FOXP1 expression and elevating GNG7 expression during preeclampsia. Mol Cell Biol. 2020;41(1):e00236-20.
Crossref Google Scholar
44

Obrist D, Nienhaus A, Zamaro E, et al. Determinants for a successful Sémont maneuver: an In vitro study with a semicircular canal model. Front Neurol. 2016;7:150.
Crossref Google Scholar
45

Tsai KL, Sun YJ, Huang CY, et al. Crystal structure of the human FOXO3a-DBD/DNA complex suggests the effects of post-translational modification. Nucleic Acids Res. 2007;35(20):6984-6994.
Crossref Google Scholar
46

Liang H, Zhang L, Wang H, et al. Inhibitory effect of gardenoside on free fatty acid-induced steatosis in HepG2 hepatocytes. Int J Mol Sci. 2015;16(11):27749-27756.
Crossref Google Scholar
47

Verovskaya EV, Dellorusso PV, Passegué E. Losing sense of self and surroundings: hematopoietic stem cell aging and leukemic transformation. Trends Mol Med. 2019;25(6):494-515.
Crossref Google Scholar
48

Han X, Kuang Y, Chen H, et al. p19INK4d: More than just a cyclin-dependent kinase inhibitor. Curr Drug Targets. 2020;21(1):96-102.
Crossref Google Scholar
49

Dai YJ, Wang YY, Huang JY, et al. Conditional knockin of Dnmt3a R878H initiates acute myeloid leukemia with mTOR pathway involvement. Proc Natl Acad Sci U S A. 2017;114(20):5237-5242.
Crossref Google Scholar
50

Ge Z, Song C, Ding Y, et al. Dual targeting of MTOR as a novel therapeutic approach for high-risk B-cell acute lymphoblastic leukemia. Leukemia. 2021;35(5):1267-1278.
Crossref Google Scholar
51

Lechman ER, Gentner B, Ng SWK, et al. miR-126 regulates distinct self-renewal outcomes in normal and malignant hematopoietic stem cells. Cancer Cell. 2016;29(2):214-228.
Crossref Google Scholar
52

Hoshii T, Tadokoro Y, Naka K, et al. mTORC1 is essential for leukemia propagation but not stem cell self-renewal. J Clin Invest. 2012;122(6):2114-2129.
Crossref Google Scholar
53

Fu Z, Tindall DJ. FOXOs, cancer and regulation of apoptosis. Oncogene. 2008;27(16):2312-2319.
Crossref Google Scholar
54

Fang Y, Yang Y, Hua C, et al. Rictor has a pivotal role in maintaining quiescence as well as stemness of leukemia stem cells in MLL-driven leukemia. Leukemia. 2017;31(2):414-422.
Crossref Google Scholar
55

Manchado E, Weissmueller S, Morris 4th JP, et al. A combinatorial strategy for treating KRAS-mutant lung cancer. Nature. 2016;534(7609):647-651.
Crossref Google Scholar
56

Theruvath J, Menard M, Smith BAH, et al. Anti-GD2 synergizes with CD47 blockade to mediate tumor eradication. Nat Med. 2022;28(2):333-344.
Crossref Google Scholar
57

Zhang S, Zhou L, Hong B, et al. Small-molecule NSC59984 restores p53 pathway signaling and antitumor effects against colorectal cancer via p73 activation and degradation of mutant p53. Cancer Res. 2015;75(18):3842-3852.
Crossref Google Scholar
58

Chen Y, Wang J, Wang Y, et al. A propolis-derived small molecule ameliorates metabolic syndrome in obese mice by targeting the CREB/CRTC2 transcriptional complex. Nat Commun. 2022;13(1):246.
Crossref Google Scholar
59

Sheng Y, Yu C, Liu Y, et al. FOXM1 regulates leukemia stem cell quiescence and survival in MLL-rearranged AML. Nat Commun. 2020;11(1):928.
Crossref Google Scholar
60

Shen T, Lei T, Chen L, et al. Gardenoside hinders caspase-1-mediated hepatocyte pyroptosis through the CTCF/DPP4 signaling pathway. Front Physiol. 2021;12:669202.
Crossref Google Scholar
61

Yu M, Su B, Zhang X. Gardenoside suppresses the pain in rats model of chronic constriction injury by regulating the P2X3 and P2X7 receptors. J Recept Signal Transduction. 2018;38(3):198-203.
Crossref Google Scholar
Genes & Diseases
Volume 11 Issue 1,
January 2024
Pages 397-412
DOI: 10.1016/j.gendis.2023.01.002
Cite this article:
Chen Z, Guo Q, Huang S, et al. Overcoming adaptive resistance in AML by synergistically targeting FOXO3A-GNG7-mTOR axis with FOXO3A inhibitor Gardenoside and rapamycin. Genes & Diseases, 2024, 11(1): 397-412. https://doi.org/10.1016/j.gendis.2023.01.002

329

Views

4

Downloads

5

Crossref

4

Web of Science

4

Scopus

0

CSCD

Altmetrics
Received: 04 November 2022
Accepted: 02 January 2023
Published: 25 January 2023
© 2023 The Authors.

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Return