Login Register Cart 0
Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

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

Identification of AHSA1 as a Potential Therapeutic Target for Breast Cancer: Bioinformatics Analysis and in vitro Studies

Author(s): Wei Shi, Lu Qi, Xiong-Bin You, Yu-Chi Chen, Yu-Lian Xu, Wei-Bang Yu, Mu-Yang Huang, Hong Zhao* and Jin-Jian Lu*

Volume 22, Issue 2, 2022

Published on: 14 February, 2022

Page: [142 - 152] Pages: 11

DOI: 10.2174/1568009622666220114151058

Price: $65

Abstract

Background: Shenling Baizhu Powder (SBP), a famous Traditional Chinese Medicine (TCM) formulation, has been widely used in the adjuvant treatment of cancers, including breast cancer. This study aims to identify potential new targets for breast cancer treatment based on the network pharmacology of SBP.

Methods: By analyzing the relationship between herbs and target proteins, potential targets of multiple herbs in SBP were identified by network pharmacology analysis. Besides, by comparing the data of breast cancer tissue with normal tissue, upregulated genes in two breast cancer expression profiles were found. Thereafter, the expression level and prognosis of activator of heat shock protein 90 (HSP90) ATPase activity 1 (AHSA1) were further analyzed in breast cancer by bioinformatics analysis, and the network module of AHSA1 binding protein was constructed. Furthermore, the effect of knocking down AHSA1 on the proliferation, migration, and invasion of breast cancer cells was verified by MTT, clone formation assay, and transwell assay.

Results: Vascular endothelial growth factor A (VEGFA), intercellular adhesion molecule 1 (ICAM1), chemokine (C-X-C motif) ligand 8 (CXCL8), AHSA1, and serpin family E member 1 (SERPINE1) were associated with multiple herbs in SBP. AHSA1 was remarkably upregulated in breast cancer tissues and positively correlated with poor overall survival and disease metastasis- free survival. Furthermore, knockdown of AHSA1 significantly inhibited the migration and invasion in MCF-7 and MDA-MB-231 breast cancer cells but had no obvious effect on proliferation. In addition, among the proteins that bind to AHSAl, the network composed of proteasome, chaperonin, and heat shock proteins is closely connected, and these proteins are associated with poor prognosis in a variety of cancers.

Conclusion: AHSA1 is positively correlated with breast cancer progression and might act as a novel therapeutic target for breast cancer.

Keywords: AHSA1, migration, invasion, network pharmacology, breast cancer, Shenling Baizhu Powder.

« Previous Next »
Graphical Abstract

[1]
Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[2]
Daily, K.; Douglas, E.; Romitti, P.A.; Thomas, A. Epidemiology of de novo metastatic breast cancer. Clin. Breast Cancer, 2021, 21(4), 302-308.
[http://dx.doi.org/10.1016/j.clbc.2021.01.017] [PMID: 33750642]
[3]
Waks, A.G.; Winer, E.P. Breast cancer treatment: A review. JAMA, 2019, 321(3), 288-300.
[http://dx.doi.org/10.1001/jama.2018.19323] [PMID: 30667505]
[4]
Li, X.L.; Guo, X.Q.; Wang, H.R.; Chen, T.; Mei, N. Aristolochic acid-induced genotoxicity and toxicogenomic changes in rodents. World J. Tradit. Chin. Med., 2020, 6(1), 12-25.
[http://dx.doi.org/10.4103/wjtcm.wjtcm_33_19] [PMID: 32258091]
[5]
Xu, D.D.; Hou, X.Y.; Wang, O.; Wang, D.; Li, D.T.; Qin, S.Y.; Lv, B.; Dai, X.M.; Zhang, Z.J.; Wan, J.B.; Xu, F.G. A four-component combination derived from Huang-Qin decoction significantly enhances anticancer activity of irinotecan. Chin. J. Nat. Med., 2021, 19(5), 364-375.
[http://dx.doi.org/10.1016/S1875-5364(21)60034-1] [PMID: 33941341]
[6]
Li, Z.; Feiyue, Z.; Gaofeng, L. Traditional chinese medicine and lung cancer-from theory to practice. Biomed. Pharmacother., 2021, 137, 111381.
[http://dx.doi.org/10.1016/j.biopha.2021.111381] [PMID: 33601147]
[7]
Zhang, Y.; Lou, Y.; Wang, J.; Yu, C.; Shen, W. Research status and molecular mechanism of the traditional Chinese medicine and antitumor therapy combined strategy based on tumor microenvironment. Front. Immunol., 2021, 11, 609705.
[http://dx.doi.org/10.3389/fimmu.2020.609705] [PMID: 33552068]
[8]
Wan, L.Q.; Tan, Y.; Jiang, M.; Hua, Q. The prognostic impact of traditional Chinese medicine monomers on tumor-associated macrophages in non-small cell lung cancer. Chin. J. Nat. Med., 2019, 17(10), 729-737.
[http://dx.doi.org/10.1016/S1875-5364(19)30089-5] [PMID: 31703753]
[9]
Wang, Y.; Zhang, S.; Zhou, Q.; Meng, M.; Chen, W. Efficacy of shenlingbaizhu formula on irritable bowel syndrome: A systematic review. J. Tradit. Chin. Med., 2020, 40(6), 897-907.
[PMID: 33258340]
[10]
Yang, L.; Song, Y.; Jin, P.; Liu, Y.; Wang, Y.; Qiao, H.; Huang, Y. Shen-Ling-Bai-Zhu-San for ulcerative colitis: Protocol for a systematic review and meta-analysis. Medicine (Baltimore), 2018, 97(38), e12337.
[http://dx.doi.org/10.1097/MD.0000000000012337] [PMID: 30235688]
[11]
Fan, X.; Yang, Z.; Shi, Y. Shenling Baizhu San combined with chemotherapy, symptomatic treatment of cancer randomized controlled study. J Pract Tradit Chin Int., 2013, 27, 25-27.
[12]
Lin, X.; Xu, W.; Shao, M.; Fan, Q.; Wen, G.; Li, C.; Jing, L.; Sun, X. Shenling Baizhu San supresses colitis associated colorectal cancer through inhibition of epithelial-mesenchymal transition and myeloid-derived suppressor infiltration. BMC Complement. Altern. Med., 2015, 15, 126.
[http://dx.doi.org/10.1186/s12906-015-0649-9] [PMID: 25897964]
[13]
Zhao, J.; Lv, C.; Wu, Q.; Zeng, H.; Guo, X.; Yang, J.; Tian, S.; Zhang, W. Computational systems pharmacology reveals an antiplatelet and neuroprotective mechanism of Deng-Zhan-Xi-Xin injection in the treatment of ischemic stroke. Pharmacol. Res., 2019, 147, 104365.
[http://dx.doi.org/10.1016/j.phrs.2019.104365] [PMID: 31348992]
[14]
Hopkins, A.L. Network pharmacology. Nat. Biotechnol., 2007, 25(10), 1110-1111.
[http://dx.doi.org/10.1038/nbt1007-1110] [PMID: 17921993]
[15]
Li, S.; Zhang, B. Traditional Chinese medicine network pharmacology: Theory, methodology and application. Chin. J. Nat. Med., 2013, 11(2), 110-120.
[http://dx.doi.org/10.1016/S1875-5364(13)60037-0] [PMID: 23787177]
[16]
Yang, B.; Wang, N.; Wang, S.; Li, X.; Zheng, Y.; Li, M.; Song, J.; Zhang, F.; Mei, W.; Lin, Y.; Wang, Z. Network-pharmacology-based identification of caveolin-1 as a key target of Oldenlandia diffusa to suppress breast cancer metastasis. Biomed. Pharmacother., 2019, 112, 108607.
[http://dx.doi.org/10.1016/j.biopha.2019.108607] [PMID: 30784915]
[17]
Chen, J.J.; Shang, X.Y.; Han, F.Y.; Zhang, Y.; Zhao, D.; Yao, G.D.; Song, S.J. Network pharmacology predicted HDAC6 as a potential target of flavones from Daphne giraldii on hepatocellular carcinoma. Nat. Prod. Res., 2021, 35(18), 3171-3175.
[http://dx.doi.org/10.1080/14786419.2019.1693563] [PMID: 31741408]
[18]
Wandinger, S.K.; Richter, K.; Buchner, J. The Hsp90 chaperone machinery. J. Biol. Chem., 2008, 283(27), 18473-18477.
[http://dx.doi.org/10.1074/jbc.R800007200] [PMID: 18442971]
[19]
Maloney, A.; Workman, P. HSP90 as a new therapeutic target for cancer therapy: The story unfolds. Expert Opin. Biol. Ther., 2002, 2(1), 3-24.
[http://dx.doi.org/10.1517/14712598.2.1.3] [PMID: 11772336]
[20]
Panaretou, B.; Siligardi, G.; Meyer, P.; Maloney, A.; Sullivan, J.K.; Singh, S.; Millson, S.H.; Clarke, P.A.; Naaby-Hansen, S.; Stein, R.; Cramer, R.; Mollapour, M.; Workman, P.; Piper, P.W.; Pearl, L.H.; Prodromou, C. Activation of the ATPase activity of hsp90 by the stress-regulated cochaperone aha1. Mol. Cell, 2002, 10(6), 1307-1318.
[http://dx.doi.org/10.1016/S1097-2765(02)00785-2] [PMID: 12504007]
[21]
Tripathi, V.; Darnauer, S.; Hartwig, N.R.; Obermann, W.M. Aha1 can act as an autonomous chaperone to prevent aggregation of stressed proteins. J. Biol. Chem., 2014, 289(52), 36220-36228.
[http://dx.doi.org/10.1074/jbc.M114.590141] [PMID: 25378400]
[22]
Xu, W.; Beebe, K.; Chavez, J.D.; Boysen, M.; Lu, Y.; Zuehlke, A.D.; Keramisanou, D.; Trepel, J.B.; Prodromou, C.; Mayer, M.P.; Bruce, J.E.; Gelis, I.; Neckers, L. Hsp90 middle domain phosphorylation initiates a complex conformational program to recruit the ATPase-stimulating cochaperone Aha1. Nat. Commun., 2019, 10(1), 2574.
[http://dx.doi.org/10.1038/s41467-019-10463-y] [PMID: 31189925]
[23]
Shao, J.; Wang, L.; Zhong, C.; Qi, R.; Li, Y. AHSA1 regulates proliferation, apoptosis, migration, and invasion of osteosarcoma. Biomed. Pharmacother., 2016, 77, 45-51.
[http://dx.doi.org/10.1016/j.biopha.2015.11.008] [PMID: 26796264]
[24]
Zheng, D.; Liu, W.; Xie, W.; Huang, G.; Jiang, Q.; Yang, Y.; Huang, J.; Xing, Z.; Yuan, M.; Wei, M.; Li, Y.; Yin, J.; Shen, J.; Shi, Z. AHA1 upregulates IDH1 and metabolic activity to promote growth and metastasis and predicts prognosis in osteosarcoma. Signal Transduct. Target. Ther., 2021, 6(1), 25.
[http://dx.doi.org/10.1038/s41392-020-00387-1] [PMID: 33468990]
[25]
Xiang, Y.; Guo, Z.; Zhu, P.; Chen, J.; Huang, Y. Traditional Chinese medicine as a cancer treatment: Modern perspectives of ancient but advanced science. Cancer Med., 2019, 8(5), 1958-1975.
[http://dx.doi.org/10.1002/cam4.2108] [PMID: 30945475]
[26]
Zhang, R.; Zhu, X.; Bai, H.; Ning, K. Network pharmacology databases for traditional Chinese medicine: Review and assessment. Front. Pharmacol., 2019, 10, 123.
[http://dx.doi.org/10.3389/fphar.2019.00123] [PMID: 30846939]
[27]
Li, S. Network pharmacology evaluation method guidance-draft. World J. Tradit. Chin. Med., 2021, 7(1), 146.
[http://dx.doi.org/10.4103/wjtcm.wjtcm_11_21]
[28]
Zhang, Q.; Lu, S.; Li, T.; Yu, L.; Zhang, Y.; Zeng, H.; Qian, X.; Bi, J.; Lin, Y. ACE2 inhibits breast cancer angiogenesis via suppressing the VEGFa/VEGFR2/ERK pathway. J. Exp. Clin. Cancer Res., 2019, 38(1), 173.
[http://dx.doi.org/10.1186/s13046-019-1156-5] [PMID: 31023337]
[29]
Rosette, C.; Roth, R.B.; Oeth, P.; Braun, A.; Kammerer, S.; Ekblom, J.; Denissenko, M.F. Role of ICAM1 in invasion of human breast cancer cells. Carcinogenesis, 2005, 26(5), 943-950.
[http://dx.doi.org/10.1093/carcin/bgi070] [PMID: 15774488]
[30]
Guo, P.; Huang, J.; Wang, L.; Jia, D.; Yang, J.; Dillon, D.A.; Zurakowski, D.; Mao, H.; Moses, M.A.; Auguste, D.T. ICAM-1 as a molecular target for triple negative breast cancer. Proc. Natl. Acad. Sci. USA, 2014, 111(41), 14710-14715.
[http://dx.doi.org/10.1073/pnas.1408556111] [PMID: 25267626]
[31]
Liu, Q.; Li, A.; Tian, Y.; Wu, J.D.; Liu, Y.; Li, T.; Chen, Y.; Han, X.; Wu, K. The CXCL8-CXCR1/2 pathways in cancer. Cytokine Growth Factor Rev., 2016, 31, 61-71.
[http://dx.doi.org/10.1016/j.cytogfr.2016.08.002] [PMID: 27578214]
[32]
Singh, J.K.; Farnie, G.; Bundred, N.J.; Simões, B.M.; Shergill, A.; Landberg, G.; Howell, S.J.; Clarke, R.B. Targeting CXCR1/2 significantly reduces breast cancer stem cell activity and increases the efficacy of inhibiting HER2 via HER2-dependent and -independent mechanisms. Clin. Cancer Res., 2013, 19(3), 643-656.
[http://dx.doi.org/10.1158/1078-0432.CCR-12-1063] [PMID: 23149820]
[33]
Azimi, I.; Petersen, R.M.; Thompson, E.W.; Roberts-Thomson, S.J.; Monteith, G.R. Hypoxia-induced reactive oxygen species mediate N-cadherin and SERPINE1 expression, EGFR signalling and motility in MDA-MB-468 breast cancer cells. Sci. Rep., 2017, 7(1), 15140.
[http://dx.doi.org/10.1038/s41598-017-15474-7] [PMID: 29123322]
[34]
Freeberg, M.A.T.; Farhat, Y.M.; Easa, A.; Kallenbach, J.G.; Malcolm, D.W.; Buckley, M.R.; Benoit, D.S.W.; Awad, H.A. Serpine1 knockdown enhances MMP activity after flexor tendon injury in mice: Implications for adhesions therapy. Sci. Rep., 2018, 8(1), 5810.
[http://dx.doi.org/10.1038/s41598-018-24144-1] [PMID: 29643421]
[35]
Loibl, S.; Gianni, L. HER2-positive breast cancer. Lancet, 2017, 389(10087), 2415-2429.
[http://dx.doi.org/10.1016/S0140-6736(16)32417-5] [PMID: 27939064]
[36]
Baker-Williams, A.J.; Hashmi, F.; Budzyński, M.A.; Woodford, M.R.; Gleicher, S.; Himanen, S.V.; Makedon, A.M.; Friedman, D.; Cortes, S.; Namek, S.; Stetler-Stevenson, W.G.; Bratslavsky, G.; Bah, A.; Mollapour, M.; Sistonen, L.; Bourboulia, D. Co-chaperones TIMP2 and AHA1 competitively regulate extracellular HSP90:Client MMP2 activity and matrix proteolysis. Cell Rep., 2019, 28(7), 1894-1906.e6.
[http://dx.doi.org/10.1016/j.celrep.2019.07.045] [PMID: 31412254]

Rights & Permissions Print Cite
Article Metrics
40
1
© 2024 Bentham Science Publishers | Privacy Policy