Login Register Cart 0
Generic placeholder image

Current Computer-Aided Drug Design

Editor-in-Chief

ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Astragaloside IV Overcomes Anlotinib Resistance in Non-small Cell Lung Cancer through miR-181a-3p/UPR-ERAD Axis

Author(s): Lihuai Wang, Tonglin Sun, Xiao Yang, Zhi Wen, Yinhui Sun* and Hua Liu*

Volume 21, Issue 4, 2025

Published on: 17 January, 2024

Page: [441 - 451] Pages: 11

DOI: 10.2174/0115734099252873231117072107

Price: $65

Abstract

Background: Astragaloside IV (AS-IV) has been shown to have a curative effect on non-small cell lung cancer (NSCLC). This study aimed to elucidate the role of AS-IV in NSCLC cell anlotinib resistance (AR).

Methods: The NSCLC/AR cells, resistant to anlotinib, have been produced. The role of AS-IV in the AR of NSCLC cells about the miR-181a-3p/unfolded protein response (UPR)- endoplasmic reticulum associated degradation (ERAD) pathway was then discussed by treating the cells with anlotinib or AS-IV, or by manipulating them with inhibitors or mimics of miR- 181a-3p, HRD1 or Derlin-1 overexpression plasmids.

Results: We found that AS-IV could suppress the AR of NSCLC cells. In addition, miR-181a- 3p was elevated in NSCLC/AR cells. Functionally, AS-IV limited the AR of NSCLC cells by reducing miR-181a-3p. Further, activation of the UPR-ERAD pathway was correlated with AR in NSCLC cells. Increased sensitivity of NSCLC cells to anlotinib caused by miR-181a-3p inhibitor could be reversed by overexpression of HRD1 or Derlin-1.

Conclusion: This research revealed a promising NSCLC/AR treatment approach by showing that AS-IV exposed NSCLC cells to anlotinib by inhibiting the miR-181a-3p/UPR-ERAD axis.

Keywords: Astragaloside IV, non-small cell lung cancer, anlotinib, miR-181a-3p, UPR, ERAD.

« Previous Next »
Graphical Abstract

[1]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
Sankar, K.; Gadgeel, S.M.; Qin, A. Molecular therapeutic targets in non-small cell lung cancer. Expert Rev. Anticancer Ther., 2020, 20(8), 647-661.
[http://dx.doi.org/10.1080/14737140.2020.1787156] [PMID: 32580596]
[3]
Inamura, K. Update on immunohistochemistry for the diagnosis of lung cancer. Cancers, 2018, 10(3), 72.
[http://dx.doi.org/10.3390/cancers10030072] [PMID: 29538329]
[4]
Gridelli, C.; Rossi, A.; Carbone, D.P.; Guarize, J.; Karachaliou, N.; Mok, T.; Petrella, F.; Spaggiari, L.; Rosell, R. Non-small-cell lung cancer. Nat. Rev. Dis. Primers, 2015, 1(1), 15009.
[http://dx.doi.org/10.1038/nrdp.2015.9] [PMID: 27188576]
[5]
Herbst, R.S.; Morgensztern, D.; Boshoff, C. The biology and management of non-small cell lung cancer. Nature, 2018, 553(7689), 446-454.
[http://dx.doi.org/10.1038/nature25183] [PMID: 29364287]
[6]
Duma, N.; Santana-Davila, R.; Molina, J.R. Non-small cell lung cancer: Epidemiology, screening, diagnosis, and treatment. Mayo Clin. Proc., 2019, 94(8), 1623-1640.
[http://dx.doi.org/10.1016/j.mayocp.2019.01.013] [PMID: 31378236]
[7]
Liang, G.; Meng, W.; Huang, X.; Zhu, W.; Yin, C.; Wang, C.; Fassan, M.; Yu, Y.; Kudo, M.; Xiao, S.; Zhao, C.; Zou, P.; Wang, Y.; Li, X.; Croce, C.M.; Cui, R. miR-196b-5p–mediated downregulation of TSPAN12 and GATA6 promotes tumor progression in non-small cell lung cancer. Proc. Natl. Acad. Sci., 2020, 117(8), 4347-4357.
[http://dx.doi.org/10.1073/pnas.1917531117] [PMID: 32041891]
[8]
Han, B.; Li, K.; Wang, Q.; Zhang, L.; Shi, J.; Wang, Z.; Cheng, Y.; He, J.; Shi, Y.; Zhao, Y.; Yu, H.; Zhao, Y.; Chen, W.; Luo, Y.; Wu, L.; Wang, X.; Pirker, R.; Nan, K.; Jin, F.; Dong, J.; Li, B.; Sun, Y. Effect of anlotinib as a third-line or further treatment on overall survival of patients with advanced non-small cell lung cancer. JAMA Oncol., 2018, 4(11), 1569-1575.
[http://dx.doi.org/10.1001/jamaoncol.2018.3039] [PMID: 30098152]
[9]
Zhang, J.; Wu, C.; Gao, L.; Du, G.; Qin, X. Astragaloside IV derived from Astragalus membranaceus: A research review on the pharmacological effects. Adv. Pharmacol., 2020, 87, 89-112.
[http://dx.doi.org/10.1016/bs.apha.2019.08.002] [PMID: 32089240]
[10]
Ren, S.; Zhang, H.; Mu, Y.; Sun, M.; Liu, P. Pharmacological effects of Astragaloside IV: A literature review. J. Tradit. Chin. Med., 2013, 33(3), 413-416.
[http://dx.doi.org/10.1016/S0254-6272(13)60189-2] [PMID: 24024343]
[11]
Li, L.; Hou, X.; Xu, R.; Liu, C.; Tu, M. Research review on the pharmacological effects of astragaloside IV. Fundam. Clin. Pharmacol., 2017, 31(1), 17-36.
[http://dx.doi.org/10.1111/fcp.12232] [PMID: 27567103]
[12]
Lai, S.T.; Wang, Y.; Peng, F. Astragaloside IV sensitizes non-small cell lung cancer cells to cisplatin by suppressing endoplasmic reticulum stress and autophagy. J. Thorac. Dis., 2020, 12(7), 3715-3724.
[http://dx.doi.org/10.21037/jtd-20-2098] [PMID: 32802451]
[13]
Yang, C.; Sun, C.; Liang, X.; Xie, S.; Huang, J.; Li, D. Integrative analysis of microRNA and mRNA expression profiles in non-small-cell lung cancer. Cancer Gene Ther., 2016, 23(4), 90-97.
[http://dx.doi.org/10.1038/cgt.2016.5] [PMID: 26964645]
[14]
Correia de Sousa, M.; Gjorgjieva, M.; Dolicka, D.; Sobolewski, C.; Foti, M. Deciphering miRNAs’ Action through miRNA Editing. Int. J. Mol. Sci., 2019, 20(24), 6249.
[http://dx.doi.org/10.3390/ijms20246249] [PMID: 31835747]
[15]
Ali Syeda, Z.; Langden, S.S.S.; Munkhzul, C.; Lee, M.; Song, S.J. Regulatory mechanism of microRNA expression in cancer. Int. J. Mol. Sci., 2020, 21(5), 1723.
[http://dx.doi.org/10.3390/ijms21051723] [PMID: 32138313]
[16]
Lee, S.S.; Cheah, Y.K. The interplay between MicroRNAs and cellular components of Tumour Microenvironment (TME) on Non-Small-Cell Lung Cancer (NSCLC) progression. J. Immunol. Res., 2019, 2019, 1-12.
[http://dx.doi.org/10.1155/2019/3046379] [PMID: 30944831]
[17]
Jin, X.; Guan, Y.; Zhang, Z.; Wang, H. Microarray data analysis on gene and miRNA expression to identify biomarkers in non-small cell lung cancer. BMC Cancer, 2020, 20(1), 329.
[http://dx.doi.org/10.1186/s12885-020-06829-x] [PMID: 32299382]
[18]
Hu, P. MiR-181a reduces radiosensitivity of non-small cell lung cancer via inhibiting PTEN. Panminerva Med., 2020, 64(3), 374-383.
[PMID: 32506887]
[19]
Qiu, L.; Chen, W.; Wu, C.; Yuan, Y.; Li, Y. Exosomes of oral squamous cell carcinoma cells containing miR-181a-3p induce muscle cell atrophy and apoptosis by transmissible endoplasmic reticulum stress signaling. Biochem. Biophys. Res. Commun., 2020, 533(4), 831-837.
[http://dx.doi.org/10.1016/j.bbrc.2020.09.066] [PMID: 32998818]
[20]
Almanza, A.; Carlesso, A.; Chintha, C.; Creedican, S.; Doultsinos, D.; Leuzzi, B.; Luís, A.; McCarthy, N.; Montibeller, L.; More, S.; Papaioannou, A.; Püschel, F.; Sassano, M.L.; Skoko, J.; Agostinis, P.; de Belleroche, J.; Eriksson, L.A.; Fulda, S.; Gorman, A.M.; Healy, S.; Kozlov, A.; Muñoz-Pinedo, C.; Rehm, M.; Chevet, E.; Samali, A. Endoplasmic reticulum stress signalling - from basic mechanisms to clinical applications. FEBS J., 2019, 286(2), 241-278.
[http://dx.doi.org/10.1111/febs.14608] [PMID: 30027602]
[21]
Papaioannou, A.; Chevet, E. Driving cancer tumorigenesis and metastasis through uPR signaling. Curr. Top. Microbiol. Immunol., 2017, 414, 159-192.
[http://dx.doi.org/10.1007/82_2017_36] [PMID: 28710693]
[22]
Jeon, Y.J.; Kim, T.; Park, D.; Nuovo, G.J.; Rhee, S.; Joshi, P.; Lee, B.K.; Jeong, J.; Suh, S.; Grotzke, J.E.; Kim, S.H.; Song, J.; Sim, H.; Kim, Y.; Peng, Y.; Jeong, Y.; Garofalo, M.; Zanesi, N.; Kim, J.; Liang, G.; Nakano, I.; Cresswell, P.; Nana-Sinkam, P.; Cui, R.; Croce, C.M. miRNA-mediated TUSC3 deficiency enhances UPR and ERAD to promote metastatic potential of NSCLC. Nat. Commun., 2018, 9(1), 5110.
[http://dx.doi.org/10.1038/s41467-018-07561-8] [PMID: 30504895]
[23]
Pustovalova, M.; Alhaddad, L.; Smetanina, N.; Chigasova, A.; Blokhina, T.; Chuprov-Netochin, R.; Osipov, A.N.; Leonov, S. The p53–53BP1-related survival of A549 and H1299 human lung cancer cells after multifractionated radiotherapy demonstrated different response to additional acute X-ray exposure. Int. J. Mol. Sci., 2020, 21(9), 3342.
[http://dx.doi.org/10.3390/ijms21093342] [PMID: 32397297]
[24]
Lu, J.; Xu, W.; Qian, J.; Wang, S.; Zhang, B.; Zhang, L.; Qiao, R.; Hu, M.; Zhao, Y.; Zhao, X.; Han, B. Transcriptome profiling analysis reveals that CXCL2 is involved in anlotinib resistance in human lung cancer cells. BMC Med. Genomics, 2019, 12(S2), 38.
[http://dx.doi.org/10.1186/s12920-019-0482-y] [PMID: 30871526]
[25]
Liu, W.; Du, Y.; Wen, R.; Yang, M.; Xu, J. Drug resistance to targeted therapeutic strategies in non-small cell lung cancer. Pharmacol. Ther., 2020, 206, 107438.
[http://dx.doi.org/10.1016/j.pharmthera.2019.107438] [PMID: 31715289]
[26]
Wang, J.; Wong, Y.K.; Liao, F. What has traditional Chinese medicine delivered for modern medicine? Expert Rev. Mol. Med., 2018, 20, e4.
[http://dx.doi.org/10.1017/erm.2018.3] [PMID: 29747718]
[27]
Zhang, A.; Zheng, Y.; Que, Z.; Zhang, L.; Lin, S.; Le, V.; Liu, J.; Tian, J. Astragaloside IV inhibits progression of lung cancer by mediating immune function of Tregs and CTLs by interfering with IDO. J. Cancer Res. Clin. Oncol., 2014, 140(11), 1883-1890.
[http://dx.doi.org/10.1007/s00432-014-1744-x] [PMID: 24980548]
[28]
Ye, Q.; Su, L.; Chen, D.; Zheng, W.; Liu, Y. Astragaloside IV induced miR-134 expression reduces EMT and increases chemotherapeutic sensitivity by suppressing CREB1 signaling in colorectal cancer cell line SW-480. Cell. Physiol. Biochem., 2017, 43(4), 1617-1626.
[http://dx.doi.org/10.1159/000482025] [PMID: 29041002]
[29]
Dai, P.C.; Liu, D.L.; Zhang, L.; Ye, J.; Wang, Q.; Zhang, H.W.; Lin, X.H.; Lai, G.X. Astragaloside IV sensitizes non-small cell lung cancer cells to gefitinib potentially via regulation of SIRT6. Tumour Biol., 2017, 39(4)
[http://dx.doi.org/10.1177/1010428317697555] [PMID: 28443459]
[30]
Croce, C.M. Causes and consequences of microRNA dysregulation in cancer. Nat. Rev. Genet., 2009, 10(10), 704-714.
[http://dx.doi.org/10.1038/nrg2634] [PMID: 19763153]
[31]
Iqbal, M.A.; Arora, S.; Prakasam, G.; Calin, G.A.; Syed, M.A. MicroRNA in lung cancer: Role, mechanisms, pathways and therapeutic relevance. Mol. Aspects Med., 2019, 70, 3-20.
[http://dx.doi.org/10.1016/j.mam.2018.07.003] [PMID: 30102929]
[32]
Ping, W.; Gao, Y.; Fan, X.; Li, W.; Deng, Y.; Fu, X. MiR-181a contributes gefitinib resistance in non-small cell lung cancer cells by targeting GAS7. Biochem. Biophys. Res. Commun., 2018, 495(4), 2482-2489.
[http://dx.doi.org/10.1016/j.bbrc.2017.12.096] [PMID: 29269300]
[33]
Gu, G.; Hu, C.; Hui, K.; Zhang, H.; Chen, T.; Zhang, X.; Jiang, X. Exosomal miR-136-5p derived from anlotinib-resistant NSCLC cells confers anlotinib resistance in non-small cell lung cancer through targeting PPP2R2A. Int. J. Nanomed., 2021, 16, 6329-6343.
[http://dx.doi.org/10.2147/IJN.S321720] [PMID: 34556984]
[34]
Azumi, J.; Tsubota, T.; Sakabe, T.; Shiota, G. miR‐181a induces sorafenib resistance of hepatocellular carcinoma cells through downregulation of RASSF 1 expression. Cancer Sci., 2016, 107(9), 1256-1262.
[http://dx.doi.org/10.1111/cas.13006] [PMID: 27384977]
[35]
Clarke, H.J.; Chambers, J.E.; Liniker, E.; Marciniak, S.J. Endoplasmic reticulum stress in malignancy. Cancer Cell, 2014, 25(5), 563-573.
[http://dx.doi.org/10.1016/j.ccr.2014.03.015] [PMID: 24823636]
[36]
Wang, M.; Kaufman, R.J. The impact of the endoplasmic reticulum protein-folding environment on cancer development. Nat. Rev. Cancer, 2014, 14(9), 581-597.
[http://dx.doi.org/10.1038/nrc3800] [PMID: 25145482]
[37]
Olzmann, J.A.; Kopito, R.R.; Christianson, J.C. The mammalian endoplasmic reticulum-associated degradation system. Cold Spring Harb. Perspect. Biol., 2013, 5(9), a013185.
[http://dx.doi.org/10.1101/cshperspect.a013185] [PMID: 23232094]
[38]
Kaneko, M.; Imaizumi, K.; Saito, A.; Kanemoto, S.; Asada, R.; Matsuhisa, K.; Ohtake, Y. ER stress and disease: Toward prevention and treatment. Biol. Pharm. Bull., 2017, 40(9), 1337-1343.
[http://dx.doi.org/10.1248/bpb.b17-00342] [PMID: 28867719]
[39]
Liu, L.; Yu, L.; Zeng, C.; Long, H.; Duan, G.; Yin, G.; Dai, X.; Lin, Z. E3 ubiquitin ligase HRD1 promotes lung tumorigenesis by promoting sirtuin 2 ubiquitination and degradation. Mol. Cell. Biol., 2020, 40(7), e00257-19.
[http://dx.doi.org/10.1128/MCB.00257-19] [PMID: 31932479]
[40]
Xu, L.; Wang, Z.H.; Xu, D.; Lin, G.; Li, D.R.; Wan, T.; Guo, S.L. Expression of Derlin-1 and its effect on expression of autophagy marker genes under endoplasmic reticulum stress in lung cancer cells. Cancer Cell Int., 2014, 14(1), 50.
[http://dx.doi.org/10.1186/1475-2867-14-50] [PMID: 24944523]
[41]
Gao, Q.; Li, X.; Xu, Y.; Zhang, J.; Rong, S.; Qin, Y.; Fang, J. IRE1α-targeting downregulates ABC transporters and overcomes drug resistance of colon cancer cells. Cancer Lett., 2020, 476, 67-74.
[http://dx.doi.org/10.1016/j.canlet.2020.02.007] [PMID: 32061752]

Rights & Permissions Print Cite
Article Metrics
41
2
Wayfinder Image
© 2026 Bentham Science Publishers | Privacy Policy