|Table of Contents|

The effect mechanism of resveratrol against T-cell acute lymphoblastic leukemia by Wnt/β-catenin signaling pathway

Journal Of Modern Oncology[ISSN:1672-4992/CN:61-1415/R]

Issue:
2023 01
Page:
50-57
Research Field:
Publishing date:

Info

Title:
The effect mechanism of resveratrol against T-cell acute lymphoblastic leukemia by Wnt/β-catenin signaling pathway
Author(s):
SHI Min12LI Yiyao1KANG Peiying1WANG Shaohua12WANG Wenjing1ZHANG Yuanyuan1 LI Yongjun12
1.Department of Clinical Laboratory,Second Hospital of Hebei Medical University,Hebei Shijiazhuang 050000,China;2.Key Laboratory of Laboratory Medicine of Hebei Province,Hebei Shijiazhuang 050000,China.
Keywords:
resveratrolT-cell acute lymphoblastic leukemiaMolt-4 cellJurkat cellT-ALL mice modelsWnt/β-catenin signaling pathway
PACS:
R733.71
DOI:
10.3969/j.issn.1672-4992.2023.01.008
Abstract:
Objective:To explore the roles and possible mechanisms of Wnt/β-catenin signaling pathway in resveratrol against T-cell acute lymphoblastic leukemia (T-ALL) in vitro and in vivo by cellular level and animal model.Methods:Human T-ALL cell lines (Molt-4 cells and Jurkat cells) were divided into control group,DMSO group and resveratrol treated group.C57BL/6 mice were randomly divided into three groups,including control group,T-ALL group and T-ALL mice with resveratrol treated group (resveratrol group).CCK-8 assay was performed to detect cell activity in Molt-4 cells and Jurkat cells.Mice injected with ICN1-GFP+ T-ALL cells by tail vein injection were used to establish the T-ALL model.The percentage of ICN1-GFP+ T-ALL cells in peripheral blood of mice was detected by flow cytometry.Real-time quantitative PCR (RT-PCR) was used to detect the expressions of c-Myc and Cyclin D1 in T-ALL cells and mice spleen tissues.The expressions of β-catenin,TCF-1,LEF-1,c-Myc and Cyclin D1 in T-ALL cell lines and mice spleen were detected by Western Blot.Results:The cell activity of Molt-4 cells and Jurkat cells was significantly suppressed after treating with resveratrol (P<0.01),and the inhibition effect was strengthened with the increasing dose of resveratrol (P<0.01).After treating with resveratrol,the expression of c-Myc and Cyclin D1 mRNA were significantly reduced (P<0.01).The protein expressions of β-catenin,TCF-1,LEF-1,c-Myc and Cyclin D1 in resveratrol group were reduced significantly (P<0.05).In vivo experiments,compared with the control group,the protein expressions of β-catenin,TCF-1,LEF-1,c-Myc,Cyclin D1,and the mRNA expression of c-Myc and Cyclin D1 were increased significantly in the mice spleen of T-ALL group (P<0.01).After resveratrol administration,the percentage of ICN1-GFP+ T-ALL cells in the peripheral blood of mice decreased notably (P<0.01) and the protein expression of β-catenin,TCF-1,LEF-1,c-Myc,Cyclin D1,and the mRNA expression of c-Myc,Cyclin D1 were significantly reduced in resveratrol group (P<0.01).Conclusion:In T-ALL cell lines and animal models,resveratrol may play an anti-acute T-lymphoblastic leukemia role by down-regulating the expression of β-catenin,TCF-1 and LEF-1 in the Wnt/β-catenin signaling pathway and then inhibiting the revels of traget proteins c-Myc and Cyclin D1.

References:

[1]BELVER L,FERRANDO A.The genetics and mechanisms of T cell acute lymphoblastic leukaemia[J].Nat Rev Cancer,2016,16(8):494-507.
[2]BIGAS A,GUILLN Y,SCHOCH L,et al.Revisiting β-Catenin signaling in T-cell development and T-cell acute lymphoblastic leukemia[J].Bioessays,2020,42(2):e1900099.
[3]KAVERI D,KASTNER P,DEMBL D,et al.β-Catenin activation synergizes with PTEN loss and Myc overexpression in Notch-independent T-ALL[J].Blood,2013,122(5):694-704.
[4]KONG Y,ZHAO S,TIAN H,et al.GAS2 promotes cell proliferation and invasion and suppresses apoptosis in pediatric T-cell acute lymphoblastic leukemia and activates Wnt/β-Catenin pathway[J].Onco Targets Ther,2020,13:1099-1108.
[5]GIAMBRA V,JENKINS CE,LAM SH,et al.Leukemia stem cells in T-ALL require active Hif1alpha and Wnt signaling[J].Blood,2015,125(25):3917-3927.
[6]CLEVERS H,NUSSE R.Wnt/beta-catenin signaling and disease[J].Cell,2012,149(6):1192-1205.
[7]ZHAO H,MEI X,YANG D,et al.Resveratrol inhibits inflammation after spinal cord injury via SIRT-1/NF-κB signaling pathway[J].Neurosci Lett,2021,762:136151.
[8]REN B,KWAH MX,LIU C,et al.Resveratrol for cancer therapy:Challenges and future perspectives[J].Cancer Lett,2021,515:63-72.
[9]SANTOS MA,FRANCO FN,CALDEIRA CA,et al.Antioxidant effect of resveratrol:Change in MAPK cell signaling pathway during the aging process[J].Arch Gerontol Geriatr,2021,92:104266.
[10]GENG W,GUO X,ZHANG L,et al.Resveratrol inhibits proliferation,migration and invasion of multiple myeloma cells via NEAT1-mediated Wnt/beta-catenin signaling pathway[J].Biomed Pharmacother,2018,107:484-494.
[11]PUI CH,CARROLL WL,MESHINCHI S,et al.Biology,risk stratification,and therapy of pediatric acute leukemias:an update[J].J Clin Oncol,2011,29(5):551-565.
[12]LATO MW,PRZYSUCHA A,GROSMAN S,et al.The new therapeutic strategies in pediatric T-cell acute lymphoblastic leukemia[J].Int J Mol Sci,2021,22(9):4502.
[13]WEERKAMP F,BAERT MR,NABER BA,et al.Wnt signaling in the thymus is regulated by differential expression of intracellular signaling molecules[J].Proc Natl Acad Sci USA,2006,103(9):3322-3326.
[14]STAAL FJ,SEN JM.The canonical Wnt signaling pathway plays an important role in lymphopoiesis and hematopoiesis[J].Eur J Immunol,2008,38(7):1788-1794.
[15]LUIS TC,NABER BA,ROOZEN PP,et al.Canonical Wnt signaling regulates hematopoiesis in a dosage-dependent fashion[J].Cell Stem Cell,2011,9(4):345-356.
[16]FAMILI F,BRUGMAN MH,TASKESEN E,et al.High levels of canonical Wnt signaling lead to loss of stemness and increased differentiation in hematopoietic stem cells[J].Stem Cell Reports,2016,6(5):652-659.
[17]PONGRACZ J,HARE K,HARMAN B,et al.Thymic epithelial cells provide WNT signals to developing thymocytes[J].Eur J Immunol,2003,33(7):1949-1956.
[18]SHTUTMAN M,ZHURINSKY J,SIMCHA I,et al.The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway[J].Proc Natl Acad Sci USA,1999,96(10):5522-5527.
[19]HE TC,SPARKS AB,RAGO C,et al.Identification of c-Myc as a target of the APC pathway[J].Science,1998,281(5382):1509-1512.
[20]NG OH,ERBILGIN Y,FIRTINA S,et al.Deregulated WNT signaling in childhood T-cell acute lymphoblastic leukemia[J].Blood Cancer J,2014,4:e192.
[21]TIEMESSEN MM,BAERT MR,SCHONEWILLE T,et al.The nuclear effector of Wnt-signaling,Tcf1,functions as a T-cell-specific tumor suppressor for development of lymphomas[J].PLoS Biol,2012,10(11):e1001430.
[22]YU S,ZHOU X,STEINKE FC,et al.The TCF-1 and LEF-1 transcription factors have cooperative and opposing roles in T cell development and malignancy[J].Immunity,2012,37(5):813-826.
[23]CHIARINI F,PAGANELLI F,MARTELLI AM,et al.The role played by Wnt/beta-Catenin signaling pathway in acute lymphoblastic leukemia[J].Int J Mol Sci,2020,21(3):1098.
[24]SZKUDELSKA K,DENIZIAK M,SASSEK M,et al.Resveratrol affects insulin signaling in type 2 diabetic Goto-Kakizaki rats[J].Int J Mol Sci,2021,22(5):2469.
[25]KONG D,YAN Y,HE XY,et al.Effects of resveratrol on the mechanisms of antioxidants and estrogen in Alzheimer's disease[J].Biomed Res Int,2019,2019:8983752.
[26]YUAN L,ZHOU M,HUANG D,et al.Resveratrol inhibits the invasion and metastasis of colon cancer through reversal of epithelial-mesenchymal transition via the AKT/GSK-3β/Snail signaling pathway[J].Mol Med Rep,2019,20(3):2783-2795.
[27]FU Y,CHANG H,PENG X,et al.Resveratrol inhibits breast cancer stem-like cells and induces autophagy via suppressing Wnt/beta-catenin signaling pathway[J].PLoS One,2014,9(7):e102535.
[28]MINEDA A,NISHIMURA M,KAGAWA T,et al.Resveratrol suppresses proliferation and induces apoptosis of uterine sarcoma cells by inhibiting the Wnt signaling pathway[J].Exp Ther Med,2019,17(3):2242-2246.
[29]LI Y,GUO Y,FENG Z,et al.Involvement of the PI3K/Akt/Nrf2 signaling pathway in resveratrol-mediated reversal of drug resistance in HL-60/ADR cells[J].Nutr Cancer,2019,71(6):1007-1018.
[30]GUO Z,DOSE M,KOVALOVSKY D,et al.Beta-catenin stabilization stalls the transition from double-positive to single-positive stage and predisposes thymocytes to malignant transformation[J].Blood,2007,109(12):5463-5472.
[31]GEKAS C,D' ALTRI T,ALIGUE R,et al.beta-Catenin is required for T-cell leukemia initiation and MYC transcription downstream of Notch1[J].Leukemia,2016,30(10):2002-2010.
[32]GUO X,ZHANG R,LIU J,et al.Characterization of LEF1 high expression and novel mutations in adult acute lymphoblastic leukemia[J].PLoS One,2015,10(5):e0125429.

Memo

Memo:
河北省自然科学基金(编号:H2021206455)
Last Update: 2022-11-30