Generic placeholder image

Current Pharmaceutical Biotechnology

Editor-in-Chief

ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

Research Article

Dysregulated YAP1/Hippo Pathway Contributes to Doxorubicin (ADM) Resistance in Acute Myeloid Leukemia (AML)

Author(s): Yan Song, Xi Chen*, Rui Huang and Juan Liu

Volume 24, Issue 5, 2023

Published on: 28 September, 2022

Page: [676 - 685] Pages: 10

DOI: 10.2174/1389201023666220617150346

Price: $65

Abstract

Background: Dysregulated Yes-associated protein 1 (YAP1) is closely associated with cancer progression and chemo-resistance. We aim to explore the role of YAP1/Hippo pathway in regulating doxorubicin (ADM)-resistance in acute myeloid leukemia (AML).

Methods: In this study, we established two ADM-resistant cell lines (THP-1/ADM and K562/ ADM). Then, cell viability and apoptosis were detected by MTT assay and FCM assay, respectively. Real-time PCR was performed to examine the expression of genes in the AML/ADM cells and the clinic BM samples. The levels of all related proteins were examined by Western blot.

Results: We found that the YAP1 and its downstream target genes, including EGFR, SOX2, and OCT4, were associated with ADM resistance, evidenced by the increased expression in ADMresistant AML/ADM cells and clinical BM specimens. Additionally, YAP1 ablation enhanced the promoting effects of ADM treatment on cell death in AML/ADM cells. Conversely, YAP1 increased ADM-a resistance in the original ADM-sensitive AML cells. These results may provide important new insights into understanding the role of YAP1 in regulating AML resistance by affecting CSCs characteristics.

Conclusion: In summary, we evidenced that the dysregulated YAP1/Hippo pathway influenced ADM resistance in AML. YAP1 might be a novel biomarker for the treatment of drug resistance in AML.

Keywords: Yes-associated protein 1, drug resistance, acute myeloid leukemia, Hippo signal pathway, cancer stem cells, AML

Graphical Abstract

[1]
Pelcovits A, Niroula R. Acute myeloid leukemia: A review. RI Med J 2020; 103(3): 38-40.
[PMID: 32236160]
[2]
Molica M, Breccia M, Foa R, Jabbour E, Kadia TM. Maintenance therapy in AML: The past, the present and the future. Am J Hematol 2019; 94(11): 1254-65.
[http://dx.doi.org/10.1002/ajh.25620] [PMID: 31429099]
[3]
Zhi J, Wu X, Hua W, Qun S, Hai YZ, Hao XB. MicroRNA145 promotes the apoptosis of leukemic stem cells and enhances drug resistant K562/ADM cell sensitivity to Adriamycin via the regulation of ABCE1. Int J Mol Med 2020; 46(4): 1289-300.
[4]
Wu B, Ge J, Zhang Z, et al. Combination of sodium selenite and doxorubicin prodrug ac-phe-lys-pabc-adm affects gastric cancer cell apoptosis in xenografted mice. BioMed Res Int 2019; 2019: 2486783.
[http://dx.doi.org/10.1155/2019/2486783] [PMID: 31531348]
[5]
Srdic-Rajic T, Tisma-Miletic N, Cavic M, et al. Sensitization of K562 leukemia cells to doxorubicin by the Viscum album extract. Phytother Res 2016; 30(3): 485-95.
[http://dx.doi.org/10.1002/ptr.5554] [PMID: 26692465]
[6]
Carvalho C, Santos RX, Cardoso S, et al. Doxorubicin: The good, the bad and the ugly effect. Curr Med Chem 2009; 16(25): 3267-85.
[http://dx.doi.org/10.2174/092986709788803312] [PMID: 19548866]
[7]
Meredith AM, Dass CR. Increasing role of the cancer chemotherapeutic doxorubicin in cellular metabolism. J Pharm Pharmacol 2016; 68(6): 729-41.
[http://dx.doi.org/10.1111/jphp.12539] [PMID: 26989862]
[8]
Tian Z, Yang Y, Yang Y, et al. High cumulative doxorubicin dose for advanced soft tissue sarcoma. BMC Cancer 2020; 20(1): 1139.
[http://dx.doi.org/10.1186/s12885-020-07663-x] [PMID: 33228579]
[9]
Paubelle E, Zylbersztejn F, Maciel TT, et al. Vitamin D receptor controls cell stemness in acute myeloid leukemia and in normal bone marrow. Cell Rep 2020; 30(3): 739-754.e4.
[http://dx.doi.org/10.1016/j.celrep.2019.12.055] [PMID: 31968250]
[10]
Wang FF, Zhang ZW, Leung WT, et al. Hydroxychloroquine reverses the drug resistance of leukemic K562/ADM cells by inhibiting autophagy. Mol Med Rep 2019; 20(4)
[11]
Feng Z, Chen Q. Raised CD40L expression attenuates drug resistance in Adriamycin-resistant THP-1 cells. Exp Ther Med 2020; 19(3): 2188-94.
[http://dx.doi.org/10.3892/etm.2020.8452] [PMID: 32104283]
[12]
Zhou W, Xu S, Chen X, Wang C. HOTAIR suppresses PTEN via DNMT3b and confers drug resistance in acute myeloid leukemia. Hematology 2021; 26(1): 170-8.
[http://dx.doi.org/10.1080/16078454.2021.1880733] [PMID: 33538241]
[13]
Zhang X, Chen J, Jiang S, et al. N-acetyltransferase 10 enhances doxorubicin resistance in human hepatocellular carcinoma cell lines by promoting the epithelial-to-mesenchymal transition. Oxid Med Cell Longev 2019; 2019: 7561879.
[http://dx.doi.org/10.1155/2019/7561879] [PMID: 31354912]
[14]
Wang L, Luo Y, Zheng Y, et al. Long non-coding RNA LINC00426 contributes to doxorubicin resistance by sponging miR-4319 in osteosarcoma. Biol Direct 2020; 15(1): 11.
[http://dx.doi.org/10.1186/s13062-020-00265-4] [PMID: 32620145]
[15]
Long J, Ji Z, Jiang K, Wang Z, Meng G. miR-193b modulates resistance to doxorubicin in human breast cancer cells by downregulating MCL-1. BioMed Res Int 2015; 2015: 373574.
[http://dx.doi.org/10.1155/2015/373574] [PMID: 26526790]
[16]
Davies GF, Berg A, Postnikoff SD, et al. TFPI1 mediates resistance to doxorubicin in breast cancer cells by inducing a hypoxic-like response. PLoS One 2014; 9(1): e84611.
[http://dx.doi.org/10.1371/journal.pone.0084611] [PMID: 24489651]
[17]
Huo X, Zhang Q, Liu AM, et al. Overexpression of Yes-associated protein confers doxorubicin resistance in hepatocellullar carcinoma. Oncol Rep 2013; 29(2): 840-6.
[http://dx.doi.org/10.3892/or.2012.2176] [PMID: 23232767]
[18]
Shibata M, Ham K, Hoque MO. A time for YAP1: Tumorigenesis, immunosuppression and targeted therapy. Int J Cancer 2018; 143(9): 2133-44.
[http://dx.doi.org/10.1002/ijc.31561] [PMID: 29696628]
[19]
Chen X, Li Y, Luo J, Hou N. Molecular mechanism of hippo-YAP1/TAZ pathway in heart development, disease, and regeneration. Front Physiol 2020; 11: 389.
[http://dx.doi.org/10.3389/fphys.2020.00389] [PMID: 32390875]
[20]
Meng Z, Moroishi T, Guan KL. Mechanisms of Hippo pathway regulation. Genes Dev 2016; 30(1): 1-17.
[http://dx.doi.org/10.1101/gad.274027.115] [PMID: 26728553]
[21]
Ma S, Meng Z, Chen R, Guan KL. The hippo pathway: Biology and pathophysiology. Annu Rev Biochem 2019; 88(1): 577-604.
[http://dx.doi.org/10.1146/annurev-biochem-013118-111829] [PMID: 30566373]
[22]
Taha Z, Janse van Rensburg HJ, Yang X. The Hippo pathway: Immunity and cancer. Cancers 2018; 10(4): 94.
[http://dx.doi.org/10.3390/cancers10040094] [PMID: 29597279]
[23]
Calses PC, Crawford JJ, Lill JR, Dey A. Hippo pathway in cancer: Aberrant regulation and therapeutic opportunities. Trends Cancer 2019; 5(5): 297-307.
[http://dx.doi.org/10.1016/j.trecan.2019.04.001] [PMID: 31174842]
[24]
Schlegelmilch K, Mohseni M, Kirak O, et al. YAP1 acts downstream of α-catenin to control epidermal proliferation. Cell 2011; 144(5): 782-95.
[http://dx.doi.org/10.1016/j.cell.2011.02.031] [PMID: 21376238]
[25]
Lv X, He C, Huang C, et al. Timely expression and activation of YAP1 in granulosa cells is essential for ovarian follicle development. FASEB J 2019; 33(9): 10049-64.
[http://dx.doi.org/10.1096/fj.201900179RR] [PMID: 31199671]
[26]
Zhou Y, Zhang J, Li H, et al. AMOTL1 enhances YAP1 stability and promotes YAP1-driven gastric oncogenesis. Oncogene 2020; 39(22): 4375-89.
[http://dx.doi.org/10.1038/s41388-020-1293-5] [PMID: 32313226]
[27]
Lin L, Sabnis AJ, Chan E, et al. The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies. Nat Genet 2015; 47(3): 250-6.
[http://dx.doi.org/10.1038/ng.3218] [PMID: 25665005]
[28]
Yoshida M, Horiguchi H, Kikuchi S, et al. miR-7977 inhibits the Hippo-YAP signaling pathway in bone marrow mesenchymal stromal cells. PLoS One 2019; 14(3): e0213220.
[http://dx.doi.org/10.1371/journal.pone.0213220] [PMID: 30835743]
[29]
Pan Y, Ma S, Cao K, et al. Therapeutic approaches targeting cancer stem cells. J Cancer Res Ther 2018; 14(7): 1469-75.
[http://dx.doi.org/10.4103/jcrt.JCRT_976_17] [PMID: 30589025]
[30]
Phi LTH, Sari IN, Yang YG, et al. Cancer Stem Cells (CSC) in drug resistance and their therapeutic implications in cancer treatment. Stem Cells Int 2018; 2018: 5416923.
[http://dx.doi.org/10.1155/2018/5416923] [PMID: 29681949]
[31]
Najafi M, Mortezaee K, Majidpoor J. Cancer Stem Cell (CSC) resistance drivers. Life Sci 2019; 234: 116781.
[http://dx.doi.org/10.1016/j.lfs.2019.116781] [PMID: 31430455]
[32]
Prieto-Vila M, Takahashi RU, Usuba W, Kohama I, Ochiya T. Drug resistance driven by cancer stem cells and their niche. Int J Mol Sci 2017; 18(12): 2574.
[http://dx.doi.org/10.3390/ijms18122574] [PMID: 29194401]
[33]
Palomeras S, Ruiz-Martínez S, Puig T. Targeting breast cancer stem cells to overcome treatment resistance. Molecules 2018; 23(9): E2193.
[http://dx.doi.org/10.3390/molecules23092193] [PMID: 30200262]
[34]
Song S, Ajani JA, Honjo S, et al. Hippo coactivator YAP1 upregulates SOX9 and endows esophageal cancer cells with stem-like properties. Cancer Res 2014; 74(15): 4170-82.
[http://dx.doi.org/10.1158/0008-5472.CAN-13-3569] [PMID: 24906622]
[35]
Guimei M, Alrouh S, Saber-Ayad M, et al. Inhibition of Yes-Associated Protein-1 (YAP1) enhances the response of invasive breast cancer cells to the standard therapy. Breast Cancer 2020; 12: 189-99.
[http://dx.doi.org/10.2147/BCTT.S268926] [PMID: 33173331]
[36]
Liu H, Liu M, Zhang J, Liang Y. Downregulated miR-130a enhances the sensitivity of acute myeloid leukemia cells to Adriamycin. Mol Med Rep 2020; 22(4): 2810-6.
[http://dx.doi.org/10.3892/mmr.2020.11375] [PMID: 32945422]
[37]
Shang J, Chen WM, Liu S, et al. CircPAN3 contributes to drug resistance in acute myeloid leukemia through regulation of autophagy. Leuk Res 2019; 85: 106198.
[http://dx.doi.org/10.1016/j.leukres.2019.106198] [PMID: 31401408]
[38]
Shang J, Chen WM, Wang ZH, Wei TN, Chen ZZ, Wu WB. CircPAN3 mediates drug resistance in acute myeloid leukemia through the miR-153-5p/miR-183-5p-XIAP axis. Exp Hematol 2019; 70: 42-54.
[39]
Hu F, Li C, Zheng X, et al. Lung adenocarcinoma resistance to therapy with EGFR-tyrosine kinase inhibitors is related to increased expression of cancer stem cell markers SOX2, OCT4 and NANOG. Oncol Rep 2020; 43(2): 727-35.
[PMID: 31894290]
[40]
García P, Rosa L, Vargas S, et al. Hippo-YAP1 is a prognosis marker and potentially targetable pathway in advanced gallbladder cancer. Cancers 2020; 12(4): E778.
[http://dx.doi.org/10.3390/cancers12040778] [PMID: 32218280]
[41]
Zhang HX, Yang JJ, Zhang SA, et al. HIF-1α promotes inflammatory response of chronic obstructive pulmonary disease by activating EGFR/PI3K/AKT pathway. Eur Rev Med Pharmacol Sci 2018; 22(18): 6077-84.
[PMID: 30280794]
[42]
Islam SS, Uddin M, Noman ASM, et al. Antibody-drug conjugate T-DM1 treatment for HER2+ breast cancer induces ROR1 and confers resistance through activation of Hippo transcriptional coactivator YAP1. EBioMedicine 2019; 43: 211-24.
[http://dx.doi.org/10.1016/j.ebiom.2019.04.061] [PMID: 31085100]
[43]
Zhong J, Zhang J, Yu X, Zhang X, Dian L. Olmutinib reverses doxorubicin resistance in ETS1-overexpressing leukemia cells. Med Sci Monit 2020; 26: e924922.
[http://dx.doi.org/10.12659/MSM.924922] [PMID: 32830792]
[44]
Hanušová V, Boušová I, Skálová L. Possibilities to increase the effectiveness of doxorubicin in cancer cells killing. Drug Metab Rev 2011; 43(4): 540-57.
[http://dx.doi.org/10.3109/03602532.2011.609174] [PMID: 21942373]
[45]
Lu T, Li Z, Yang Y, et al. The Hippo/YAP1 pathway interacts with FGFR1 signaling to maintain stemness in lung cancer. Cancer Lett 2018; 423: 36-46.
[http://dx.doi.org/10.1016/j.canlet.2018.02.015] [PMID: 29452146]
[46]
Zhang J, Ma X, Zhou R, Zhou Y. TRPS1 and YAP1 regulate cell proliferation and drug resistance of osteosarcoma via competitively binding to the target of circTADA2A - miR-129-5p. OncoTargets Ther 2020; 13: 12397-407.
[http://dx.doi.org/10.2147/OTT.S276953] [PMID: 33293831]
[47]
Wang Y, Lieberman R, Pan J, et al. miR-375 induces docetaxel resistance in prostate cancer by targeting SEC23A and YAP1. Mol Cancer 2016; 15(1): 70.
[http://dx.doi.org/10.1186/s12943-016-0556-9] [PMID: 27832783]
[48]
Wang Y, Xin D, Zhou L. LncRNA LINC00152 increases the aggressiveness of human retinoblastoma and enhances carboplatin and adriamycin resistance by regulating mir-613/Yes-Associated Protein 1 (YAP1) axis. Med Sci Monit 2020; 26: e920886.
[http://dx.doi.org/10.12659/MSM.920886] [PMID: 32541644]
[49]
Ooki A, Del Carmen Rodriguez Pena M, Marchionni L, et al. YAP1 and COX2 coordinately regulate urothelial cancer stem-like cells. Cancer Res 2018; 78(1): 168-81.
[http://dx.doi.org/10.1158/0008-5472.CAN-17-0836] [PMID: 29180467]
[50]
Hou H, Kang Y, Li Y, Zeng Y, Ding G, Shang J. miR-33a expression sensitizes Lgr5+ HCC-CSCs to doxorubicin via ABCA1. Neoplasma 2017; 64(1): 81-91.
[http://dx.doi.org/10.4149/neo_2017_110] [PMID: 27881008]
[51]
Yi ZA, Dya YA, Zhao XS, Vimla B, Elena VB, Alexander VX. Biology and medicine, eradication of cancer stem cells in triple negative breast cancer using doxorubicin/pluronic polymeric micelles. Nanomedicine 2020; 24: 102124.
[52]
Lu T, Yang Y, Li Z, Lu S. MicroRNA-214-3p inhibits the stemlike properties of lung squamous cell cancer by targeting YAP1. Cancer Cell Int 2020; 20(1): 413.
[http://dx.doi.org/10.1186/s12935-020-01506-2] [PMID: 32863772]
[53]
Tsai LL, Yu CC, Chang YC, Yu CH, Chou MY. Markedly increased Oct4 and nanog expression correlates with cisplatin resistance in oral squamous cell carcinoma. J Oral Pathol Med 2011; 40(8): 621-8.
[http://dx.doi.org/10.1111/j.1600-0714.2011.01015.x] [PMID: 21342274]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy