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Protein & Peptide Letters

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ISSN (Print): 0929-8665
ISSN (Online): 1875-5305

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Research Article

(R)-9bMS Inhibited the Protein Synthesis and Autophagy of Triple Negative Breast Cancer Cells via Regulating miR-4660/mTOR Axis

Author(s): Xiangdong Bai, Guohui Han, Feng Li, Weina Li, Peng Bu, Huanhu Zhang* and Jun Xie*

Volume 30, Issue 4, 2023

Published on: 07 April, 2023

Page: [295 - 303] Pages: 9

DOI: 10.2174/0929866530666230302150750

Price: $65

Abstract

Background: Unlike other subtypes of breast cancer, triple negative breast cancer (TNBC) exhibits aggressive and metastatic behaviors and a lack of effective targeted therapeutics. (R)-9bMS, a small-molecule inhibitor of the non-receptor tyrosine kinase 2 (TNK2), significantly inhibited TNBC cell growth; however, the functional mechanism of (R)-9bMS in TNBC remains largely unknown.

Objective: To explore the functional mechanism of (R)-9bMS in TNBC.

Methods: Cell proliferation, apoptosis and xenograft tumor growth assays were performed to evaluate the effects of (R)-9bMS on TNBC. The expression levels of miRNA and protein were detected by RTqPCR or western blot, respectively. Protein synthesis was determined by analyzing the polysome profile and 35S-met incorporation.

Results: (R)-9bMS attenuated TNBC cell proliferation, induced cell apoptosis, and inhibited xenograft tumor growth. Mechanism study indicated that (R)-9bMS upregulated the expression of miR-4660 in TNBC cells. The expression of miR-4660 is lower in TNBC samples than that of the non-cancerous tissues. miR-4660 overexpression inhibited TNBC cell proliferation by targeting the mammalian target of rapamycin (mTOR), which reduced mTOR abundance in TNBC cells. Consistent with the downregulation of mTOR, exposure of (R)-9bMS inhibited the phosphorylation of p70S6K and 4E-BP1, which consequently interrupted the total protein synthesis and autophagy of TNBC cells.

Conclusion: These findings uncovered the novel working mechanism of (R)-9bMS in TNBC by attenuating mTOR signaling via up-regulating miR-4660. The potential clinical significance of (R)- 9bMS in TNBC treatment is interesting to explore.

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[1]
Elias, A.D. Triple-negative breast cancer: A short review. Am. J. Clin. Oncol., 2010, 33(6), 637-645.
[http://dx.doi.org/10.1097/COC.0b013e3181b8afcf] [PMID: 20023571]
[2]
Ismail-Khan, R.; Bui, M.M. A review of triple-negative breast cancer. Cancer Contr., 2010, 17(3), 173-176.
[http://dx.doi.org/10.1177/107327481001700305] [PMID: 20664514]
[3]
Shen, M.; Pan, H.; Chen, Y.; Xu, Y.H.; Yang, W.; Wu, Z. A review of current progress in triple-negative breast cancer therapy. Open Med., 2020, 15(1), 1143-1149.
[http://dx.doi.org/10.1515/med-2020-0138] [PMID: 33336070]
[4]
Won, K.A.; Spruck, C. Triple negative breast cancer therapy: Current and future perspectives.(Review) Int. J. Oncol., 2020, 57(6), 1245-1261.
[http://dx.doi.org/10.3892/ijo.2020.5135] [PMID: 33174058]
[5]
Griffiths, C.L.; Olin, J.L. Triple negative breast cancer: A brief review of its characteristics and treatment options. J. Pharm. Pract., 2012, 25(3), 319-323.
[http://dx.doi.org/10.1177/0897190012442062] [PMID: 22551559]
[6]
Wu, X.; Saddiq Zahari, M.; Renuse, S.; Kelkar, D.S.; Barbhuiya, M.A.; Rojas, P.L.; Stearns, V.; Gabrielson, E.; Malla, P.; Sukumar, S.; Mahajan, N.P.; Pandey, A. The non-receptor tyrosine kinase TNK2/ACK1 is a novel therapeutic target in triple negative breast cancer. Oncotarget, 2017, 8(2), 2971-2983.
[http://dx.doi.org/10.18632/oncotarget.13579] [PMID: 27902967]
[7]
Mahajan, N.P.; Coppola, D.; Kim, J.; Lawrence, H.R.; Lawrence, N.J.; Mahajan, K. Blockade of ACK1/TNK2 to squelch the survival of prostate cancer stem-like cells. Sci. Rep., 2018, 8(1), 1954.
[http://dx.doi.org/10.1038/s41598-018-20172-z] [PMID: 29386546]
[8]
Benfey, P.N. MicroRNA is here to stay. Nature, 2003, 425(6955), 244-245.
[http://dx.doi.org/10.1038/425244a] [PMID: 13679896]
[9]
Luhur, A.; Kumar, J. Advances in microRNA biology. Fly , 2008, 2(3), 123-124.
[http://dx.doi.org/10.4161/fly.6330] [PMID: 18820461]
[10]
Mohr, A.; Mott, J. Overview of microRNA biology. Semin. Liver Dis.,, 2015, 35(1), 003-011.
[http://dx.doi.org/10.1055/s-0034-1397344] [PMID: 25632930]
[11]
Xiao, Y.; MacRae, I.J. Toward a comprehensive view of MicroRNA biology. Mol. Cell, 2019, 75(4), 666-668.
[http://dx.doi.org/10.1016/j.molcel.2019.08.001] [PMID: 31442421]
[12]
Sabit, H.; Cevik, E.; Tombuloglu, H.; Abdel-Ghany, S.; Tombuloglu, G.; Esteller, M. Triple negative breast cancer in the era of miRNA. Crit. Rev. Oncol. Hematol., 2021, 157, 103196.
[http://dx.doi.org/10.1016/j.critrevonc.2020.103196] [PMID: 33307198]
[13]
Xu, J.; Wu, K.; Jia, Q.; Ding, X. Roles of miRNA and IncRNA in triple-negative breast cancer. J. Zhejiang Univ. Sci. B, 2020, 21(9), 673-689.
[http://dx.doi.org/10.1631/jzus.B1900709] [PMID: 32893525]
[14]
Du, Y.; Wei, N.; Ma, R.; Jiang, S.; Song, D. A miR-210-3p regulon that controls the Warburg effect by modulating HIF-1 and p53 activity in triple-negative breast cancer. Cell Death Dis., 2020, 11(9), 731.
[http://dx.doi.org/10.1038/s41419-020-02952-6] [PMID: 32908121]
[15]
Noyan, S.; Andac Ozketen, A.; Gurdal, H.; Gur Dedeoglu, B. miR-770-5p regulates EMT and invasion in TNBC cells by targeting DNMT3A. Cell. Signal., 2021, 83, 109996.
[http://dx.doi.org/10.1016/j.cellsig.2021.109996] [PMID: 33798630]
[16]
Huang, S.; Houghton, P.J. Targeting mTOR signaling for cancer therapy. Curr. Opin. Pharmacol., 2003, 3(4), 371-377.
[http://dx.doi.org/10.1016/S1471-4892(03)00071-7] [PMID: 12901945]
[17]
Advani, S.H. Targeting mTOR pathway: A new concept in cancer therapy. Indian J. Med. Paediatr. Oncol., 2010, 31(4), 132-136.
[http://dx.doi.org/10.4103/0971-5851.76197] [PMID: 21584218]
[18]
Tian, T.; Li, X.; Zhang, J. mTOR signaling in cancer and mTOR inhibitors in solid tumor targeting therapy. Int. J. Mol. Sci., 2019, 20(3), 755.
[http://dx.doi.org/10.3390/ijms20030755] [PMID: 30754640]
[19]
Cidado, J.; Park, B.H. Targeting the PI3K/Akt/mTOR pathway for breast cancer therapy. J. Mammary Gland Biol. Neoplasia, 2012, 17(3-4), 205-216.
[http://dx.doi.org/10.1007/s10911-012-9264-2] [PMID: 22865098]
[20]
Costa, R.L.B.; Han, H.S.; Gradishar, W.J. Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: A review. Breast Cancer Res. Treat., 2018, 169(3), 397-406.
[http://dx.doi.org/10.1007/s10549-018-4697-y] [PMID: 29417298]
[21]
Lin, Q.; Wang, J.; Childress, C.; Yang, W. The activation mechanism of ACK1 (activated Cdc42-associated tyrosine kinase 1). Biochem. J., 2012, 445(2), 255-264.
[http://dx.doi.org/10.1042/BJ20111575] [PMID: 22553920]
[22]
Chang-Qing, Y.; Jie, L.; Shi-Qi, Z.; Kun, Z.; Zi-Qian, G.; Ran, X.; Hui-Meng, L.; Ren-Bin, Z.; Gang, Z.; Da-Chuan, Y.; Chen-Yan, Z. Recent treatment progress of triple negative breast cancer. Prog. Biophys. Mol. Biol., 2020, 151, 40-53.
[http://dx.doi.org/10.1016/j.pbiomolbio.2019.11.007] [PMID: 31761352]
[23]
Davis, A.A.; Gradishar, W.J. Novel neoadjuvant treatment strategies for triple-negative breast cancer. Oncology, 2020, 34(5), 176-182.
[PMID: 32644178]
[24]
Vagia, E.; Mahalingam, D.; Cristofanilli, M. The landscape of targeted therapies in TNBC. Cancers , 2020, 12(4), 916.
[http://dx.doi.org/10.3390/cancers12040916] [PMID: 32276534]
[25]
Mo, H.; Xu, B. Progress in systemic therapy for triple-negative breast cancer. Front. Med., 2021, 15(1), 1-10.
[http://dx.doi.org/10.1007/s11684-020-0741-5] [PMID: 32789731]
[26]
Al-Othman, N.; Ahram, M.; Alqaraleh, M. Role of androgen and microRNA in triple-negative breast cancer. Breast Dis., 2020, 39(1), 15-27.
[http://dx.doi.org/10.3233/BD-190416] [PMID: 31839601]
[27]
Mei, J.; Hao, L.; Wang, H.; Xu, R.; Liu, Y.; Zhu, Y.; Liu, C. Systematic characterization of non coding RNAs in triple negative breast cancer. Cell Prolif., 2020, 53(5), e12801.
[http://dx.doi.org/10.1111/cpr.12801] [PMID: 32249490]
[28]
Qattan, A. Novel miRNA targets and therapies in the triple-negative breast cancer microenvironment: An emerging hope for a challenging disease. Int. J. Mol. Sci., 2020, 21(23), 8905.
[http://dx.doi.org/10.3390/ijms21238905] [PMID: 33255471]
[29]
Yang, X.; Zhong, W.; Cao, R. Phosphorylation of the mRNA cap-binding protein eIF4E and cancer. Cell. Signal., 2020, 73, 109689.
[http://dx.doi.org/10.1016/j.cellsig.2020.109689] [PMID: 32535199]
[30]
Tu, X.; Zhao, Y.; Li, Q.; Yu, X.; Yang, Y.; Shi, S.; Ding, Z.; Miao, Y.; Zou, Z.; Wang, X.; Jiang, J.; Du, D. Human MiR-4660 regulates the expression of alanine-glyoxylate aminotransferase and may be a biomarker for idiopathic oxalosis. Clin. Exp. Nephrol., 2019, 23(7), 890-897.
[http://dx.doi.org/10.1007/s10157-019-01723-8] [PMID: 30852714]
[31]
Weichhart, T. mTOR as regulator of lifespan, aging, and cellular senescence: A mini-review. Gerontology, 2018, 64(2), 127-134.
[http://dx.doi.org/10.1159/000484629] [PMID: 29190625]
[32]
Xu, C.; Zeng, Q.; Xu, W.; Jiao, L.; Chen, Y.; Zhang, Z.; Wu, C.; Jin, T.; Pan, A.; Wei, R.; Yang, B.; Sun, Y. miRNA-100 inhibits human bladder urothelial carcinogenesis by directly targeting mTOR. Mol. Cancer Ther., 2013, 12(2), 207-219.
[http://dx.doi.org/10.1158/1535-7163.MCT-12-0273] [PMID: 23270926]
[33]
Li, W.; Chang, J.; Wang, S.; Liu, X.; Peng, J.; Huang, D.; Sun, M.; Chen, Z.; Zhang, W.; Guo, W.; Li, J. miRNA-99b-5p suppresses liver metastasis of colorectal cancer by down-regulating mTOR. Oncotarget, 2015, 6(27), 24448-24462.
[http://dx.doi.org/10.18632/oncotarget.4423] [PMID: 26259252]
[34]
Akbarzadeh, M.; Mihanfar, A.; Akbarzadeh, S.; Yousefi, B.; Majidinia, M. Crosstalk between miRNA and PI3K/AKT/mTOR signaling pathway in cancer. Life Sci., 2021, 285, 119984.
[http://dx.doi.org/10.1016/j.lfs.2021.119984] [PMID: 34592229]
[35]
Kimball, S.R.; Jurasinski, C.V.; Lawrence, J.C., Jr; Jefferson, L.S. Insulin stimulates protein synthesis in skeletal muscle by enhancing the association of eIF-4E and eIF-4G. Am. J. Physiol. Cell Physiol., 1997, 272(2), C754-C759.
[http://dx.doi.org/10.1152/ajpcell.1997.272.2.C754] [PMID: 9124320]

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