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Current Pharmaceutical Biotechnology

Editor-in-Chief

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

Research Article

Analysis of the Differences in the Expression of mRNAs and miRNAs Associated with Drug Resistance in Endometrial Cancer Cells Treated with Salinomycin

Author(s): Piotr Januszyk*, Krzysztof Januszyk, Magdalena Wierzbik-Strońska, Dariusz Boroń and Beniamin Grabarek

Volume 22, Issue 4, 2021

Published on: 29 June, 2020

Page: [541 - 548] Pages: 8

DOI: 10.2174/1389201021666200629151008

open access plus

Abstract

Background: It is important to understand the molecular mechanisms involved in cancer drug resistance and to study the activity of new drugs, e.g. salinomycin.

Objective: The purpose of the study was to analyze changes in the expression of genes associated with drug resistance in the Ishikawa endometrial cancer cell line when treated with salinomycin. In addition, changes in the level of miRNA potentially regulating these mRNAs were evaluated.

Materials and Methods: Endometrial cancer cells were treated with 1 μM of salinomycin for 12, 24 and 48 hours periods. Untreated cells were a control culture. The molecular analysis consists of mRNA and miRNA microarray analysis and the RTqPCR technique.

Results: The following was observed about the number of mRNAs differentiating the cell culture exposed to the drug compared to a control culture: H-12 vs. C - 9 mRNAs, H_24 vs. C - 6 mRNAs, and H_48 vs. C - 1 mRNA. It was noted that 4 of the 9 differentiating mRNAs were characteristic for 12 hours of exposure to salinomycin and they correspond to the following genes: TUFT1, ABCB1, MTMR11, and MX2. After 24 hours, 2 mRNAs were characteristic for this time of incubation cells with salinomycin: TUFT1 and MYD88 and after 48 hours, SLC30A5 could also be observed.

Discussion: The highest differences in expression were indicated for TUFT1, MTMR11, and SLC30A5. The highest influence probability was determined between TUFT1 and hsa- miR-3188 (FC + 2.48), MTMR11and has-miR-16 (FC -1.74), and between SLC30A5 and hsa-miR-30d (FC -2.01).

Conclusion: Salinomycin induces changes in the activity of mRNA and miRNA participating in drug resistance; however, the observed changes in character are the expected result of anti-cancer treatment.

Keywords: Cancer drug resistance, salinomycin, micro RNA, endometrial cancer cells, RTqPCR technique, molecular analysis.

Graphical Abstract
[1]
Webb, B.J.; Sorensen, J.; Mecham, I.; Buckel, W.; Ooi, L.; Jephson, A.; Dean, N.C. Antibiotic use and outcomes after implementation of the drug resistance in pneumonia score in ED patients with community-onset pneumonia Chest, 2019, 156(5), 843-851.
[http://dx.doi.org/10.1016/j.chest.2019.04.093] [PMID: 31077649]
[2]
Holohan, C.; Van Schaeybroeck, S.; Longley, D.B.; Johnston, P.G. Cancer drug resistance: An evolving paradigm. Nat. Rev. Cancer, 2013, 13(10), 714-726.
[http://dx.doi.org/10.1038/nrc3599] [PMID: 24060863]
[3]
Smith, A.G.; Macleod, K.F. Autophagy, cancer stem cells and drug resistance. J. Pathol., 2019, 247(5), 708-718.
[http://dx.doi.org/10.1002/path.5222] [PMID: 30570140]
[4]
Baguley, B.C. Multiple drug resistance mechanisms in cancer. Mol. Biotechnol., 2010, 46(3), 308-316.
[http://dx.doi.org/10.1007/s12033-010-9321-2] [PMID: 20717753]
[5]
Soares, F.S.; Lettnin, A.P.; Wagner, E.F.; Mattozo, F.H.; Carrett-Dias, M.; Rumjanek, V.M.B.D.; Filgueira, D.M.V.B.; de Souza Votto, A.P. Multidrug resistance phenotype: Relation between phenotype induction and its characteristics in erythroleukemia cells. Cell Biol. Int., 2019, 43(2), 214-219.
[http://dx.doi.org/10.1002/cbin.11095] [PMID: 30597722]
[6]
Zhang, R.X.; Wong, H.L.; Xue, H.Y.; Eoh, J.Y.; Wu, X.Y. Nanomedicine of synergistic drug combinations for cancer therapy - Strategies and perspectives. J. Control. Release, 2016, 240, 489-503.
[http://dx.doi.org/10.1016/j.jconrel.2016.06.012] [PMID: 27287891]
[7]
Macanas-Pirard, P.; Broekhuizen, R.; González, A.; Oyanadel, C.; Ernst, D.; García, P.; Montecinos, V.P.; Court, F.; Ocqueteau, M.; Ramirez, P.; Nervi, B. Resistance of leukemia cells to cytarabine chemotherapy is mediated by bone marrow stroma, involves cell-surface equilibrative nucleoside transporter-1 removal and correlates with patient outcome. Oncotarget, 2017, 8(14), 23073-23086.
[http://dx.doi.org/10.18632/oncotarget.14981] [PMID: 28160570]
[8]
Tsui, D.W.Y.; Murtaza, M.; Wong, A.S.C.; Rueda, O.M.; Smith, C.G.; Chandrananda, D.; Soo, R.A.; Lim, H.L.; Goh, B.C.; Caldas, C.; Forshew, T.; Gale, D.; Liu, W.; Morris, J.; Marass, F.; Eisen, T.; Chin, T.M.; Rosenfeld, N. Dynamics of multiple resistance mechanisms in plasma DNA during EGFR-targeted therapies in non-small cell lung cancer. EMBO Mol. Med., 2018, 10(6), e7945.
[http://dx.doi.org/10.15252/emmm.201707945] [PMID: 29848757]
[9]
Smith, B.N.; Bhowmick, N.A. Role of EMT in metastasis and therapy resistance. J. Clin. Med., 2016, 5(2), 17.
[http://dx.doi.org/10.3390/jcm5020017] [PMID: 26828526]
[10]
Loret, N.; Denys, H.; Tummers, P.; Berx, G. The role of epithelialto- mesenchymal plasticity in ovarian cancer progression and therapy resistance. Cancers (Basel), 2019, 11(6), 838.
[http://dx.doi.org/10.3390/cancers11060838] [PMID: 31213009]
[11]
Emran, A.A.; Marzese, D.M.; Menon, D.R.; Hammerlindl, H. Ahmed. F. Richtig. E.; Schaider. H. Commonly integrated epigenetic modifications of differentially expressed genes lead to adaptive resistance in cancer. Epigenomics, 2019. , 11(7), 732-737.
[PMID: 31070054]
[12]
Chaudhry, P.; Asselin, E. Resistance to chemotherapy and hormone therapy in endometrial cancer. Endocr. Relat. Cancer, 2009, 16(2), 363-380.
[http://dx.doi.org/10.1677/ERC-08-0266] [PMID: 19190080]
[13]
Jerzak, K.J.; Duska, L.; MacKay, H.J. Endocrine therapy in endometrial cancer: An old dog with new tricks. Gynecol. Oncol., 2019, 153(1), 175-183.
[http://dx.doi.org/10.1016/j.ygyno.2018.12.018] [PMID: 30616900]
[14]
Huczyński, A.; Markowska, J.; Ramlau, R.; Sajdak, S.; Szubert, S.; Stencel, K. Salinomycyna przełom w leczeniu raka jajnika? Curr Gynecologic Oncol., 2016, 14(3), 156-161.
[15]
Fuchs, D.; Heinold, A.; Opelz, G.; Daniel, V.; Naujokat, C. Salinomycin induces apoptosis and overcomes apoptosis resistance in human cancer cells. Biochem. Biophys. Res. Commun., 2009, 390(3), 743-749.
[http://dx.doi.org/10.1016/j.bbrc.2009.10.042] [PMID: 19835841]
[16]
Kozak, J.; Wdowiak, P.; Maciejewski, R.; Torres, A. A guide for endometrial cancer cell lines functional assays using the measurements of electronic impedance. Cytotechnology, 2018, 70(1), 339-350.
[http://dx.doi.org/10.1007/s10616-017-0149-5] [PMID: 28988392]
[17]
Chitcholtan, K.; Sykes, P.H.; Evans, J.J. The resistance of intracellular mediators to doxorubicin and cisplatin are distinct in 3D and 2D endometrial cancer. J. Transl. Med., 2012, 10(1), 38.
[http://dx.doi.org/10.1186/1479-5876-10-38] [PMID: 22394685]
[18]
Sun, M.Y.; Zhu, J.Y.; Zhang, C.Y.; Zhang, M.; Song, Y.N.; Rahman, K.; Zhang, L.J.; Zhang, H. Autophagy regulated by lncRNA HOTAIR contributes to the cisplatin-induced resistance in endometrial cancer cells. Biotechnol. Lett., 2017, 39(10), 1477-1484.
[http://dx.doi.org/10.1007/s10529-017-2392-4] [PMID: 28721581]
[19]
Wcisło-Dziadecka, D.; Grabarek,B.; Zmarzły, N.; Skubis, A. Sikora. B. Kruszniewska-Rajs. C.; Kucharz. E. Influence of adalimumab on the expression profile of genes associated with the Histaminergic system in the skin fibroblasts in vitro. BioMed Res. Int., 2018, 2018, 1582173.
[20]
Betel, D.; Wilson, M.; Gabow, A.; Marks, D. S.; Sander, C. The microRNA. Org resource: Targets and expression. Nucleic acids Res., 2008, 36(suppl_1), D149-D153..
[21]
Washio, I.; Nakanishi, T.; Ishiguro, N.; Bister, B.; Tamai, I. Effect of endogenous multidrug resistance 1 and P-glycoprotein expression on anticancer drug resistance in colon cancer cell lines. Biopharm. Drug Dispos., 2019, 40(1), 32-43.
[PMID: 30556139]
[22]
Dewangan, J.; Srivastava, S.; Rath, S.K. Salinomycin: A new paradigm in cancer therapy. Tumour Biol., 2017, 39(3), 1010428317695035.
[http://dx.doi.org/10.1177/1010428317695035] [PMID: 28349817]
[23]
Mao, Z.; Wu, Y.; Zhou, J.; Xing, C. Salinomycin reduces epithelial-mesenchymal transition-mediated multidrug resistance by modifying long noncoding RNA HOTTIP expression in gastric cancer cells., Anticancer Drugs, 2019, 30(9), 892-899..
[http://dx.doi.org/10.1097/CAD.0000000000000786] [PMID: 30882398]
[24]
Dou, C.; Zhou, Z.; Xu, Q.; Liu, Z.; Zeng, Y.; Wang, Y.; Li, Q.; Wang, L.; Yang, W.; Liu, Q.; Tu, K. Hypoxia-induced TUFT1 promotes the growth and metastasis of hepatocellular carcinoma by activating the Ca2+/PI3K/AKT pathway. Oncogene, 2019, 38(8), 1239-1255.
[http://dx.doi.org/10.1038/s41388-018-0505-8] [PMID: 30250300]
[25]
Schulten, H.J.; Bakhashab, S. Meta-analysis of microarray expression studies on metformin in cancer cell lines. Int. J. Mol. Sci., 2019, 20(13), 3173.
[http://dx.doi.org/10.3390/ijms20133173] [PMID: 31261735]
[26]
Hinshaw, D.C.; Shevde, L.A. The tumor microenvironment innately modulates cancer progression., Cancer Res., 2019, 79(18), 4557- 4566..
[http://dx.doi.org/10.1158/0008-5472.CAN-18-3962] [PMID: 31350295]
[27]
Hinshaw, D.C.; Shevde, L.A. The tumor microenvironment innately modulates cancer progression., Cancer Res., 2019, 79(18), 4557- 4566..
[http://dx.doi.org/10.1158/0008-5472.CAN-18-3962] [PMID: 31350295]
[28]
Laporte, J.; Blondeau, F.; Buj-Bello, A.; Mandel, J.L. The myotubularin family: from genetic disease to phosphoinositide metabolism., Trends Genet., 2001, 17(4), 221-228..
[http://dx.doi.org/10.1016/S0168-9525(01)02245-4] [PMID: 11275328]
[29]
Pascual, J.; Turner, N. C. Targeting the PI3-kinase pathway in triple-negative breast cancer., Annals Oncol., 2019, 30(7), 1051-1060..
[http://dx.doi.org/10.1093/annonc/mdz133]
[30]
Li, Y.; Zhang, Z.; Zhang, X.; Lin, Y.; Luo, T.; Xiao, Z.; Zhou, Q. A dual PI3K/AKT/mTOR signaling inhibitor miR-99a suppresses endometrial carcinoma. Am. J. Transl. Res., 2016, 8(2), 719-731.
[PMID: 27158364]
[31]
Wang, Y.; Ren, F.; Li, B.; Song, Z.; Chen, P.; Ouyang, L. Ellagic acid exerts antitumor effects via the PI3K signaling pathway in endometrial cancer. J. Cancer, 2019, 10(15), 3303-3314.
[http://dx.doi.org/10.7150/jca.29738] [PMID: 31293633]
[32]
Hara, T.; Takeda, T.A.; Takagishi, T.; Fukue, K.; Kambe, T.; Fukada, T. Physiological roles of zinc transporters: Molecular and genetic importance in zinc homeostasis. J. Physiol. Sci., 2017, 67(2), 283-301.
[http://dx.doi.org/10.1007/s12576-017-0521-4] [PMID: 28130681]
[33]
Barresi, V.; Valenti, G.; Spampinato, G.; Musso, N.; Castorina, S.; Rizzarelli, E.; Condorelli, D.F. Transcriptome analysis reveals an altered expression profile of zinc transporters in colorectal cancer. J. Cell. Biochem., 2018, 119(12), 9707-9719.
[http://dx.doi.org/10.1002/jcb.27285] [PMID: 30129075]
[34]
Singh, C.K.; Malas, K.M.; Tydrick, C.; Siddiqui, I.A.; Iczkowski, K.A.; Ahmad, N. Analysis of zinc-exporters expression in prostate cancer. Sci. Rep., 2016, 6, 36772.
[http://dx.doi.org/10.1038/srep36772] [PMID: 27833104]
[35]
Zhao, M.; Luo, R.; Liu, Y.; Gao, L.; Fu, Z.; Fu, Q.; Luo, X.; Chen, Y.; Deng, X.; Liang, Z.; Li, X.; Cheng, C.; Liu, Z.; Fang, W. miR-3188 regulates nasopharyngeal carcinoma proliferation and chemosensitivity through a FOXO1-modulated positive feedback loop with mTOR-p-PI3K/AKT-c-JUN. Nat. Commun., 2016, 7, 11309.
[http://dx.doi.org/10.1038/ncomms11309] [PMID: 27095304]
[36]
Zhou, S.J.; Deng, Y.L.; Liang, H.F.; Jaoude, J.C.; Liu, F.Y. Hepatitis B virus X protein promotes CREB-mediated activation of miR-3188 and Notch signaling in hepatocellular carcinoma. Cell Death Differ., 2017, 24(9), 1577-1587.
[http://dx.doi.org/10.1038/cdd.2017.87] [PMID: 28574502]
[37]
Zhang, R.; Xu, J.; Zhao, J.; Bai, J. Mir-30d suppresses cell proliferation of colon cancer cells by inhibiting cell autophagy and promoting cell apoptosis. Tumour Biol., 2017, 39(6), 1010428317703984.
[http://dx.doi.org/10.1177/1010428317703984] [PMID: 28651493]
[38]
Hosseini, S.M.; Soltani, B.M.; Tavallaei, M.; Mowla, S.J.; Tafsiri, E.; Bagheri, A.; Khorshid, H.R.K. Clinically significant dysregulation of hsa-miR-30d-5p and hsa-let-7b expression in patients with surgically resected non-small cell lung cancer. Avicenna J. Med. Biotechnol., 2018, 10(2), 98-104.
[PMID: 29849986]
[39]
Klutstein, M.; Nejman, D.; Greenfield, R.; Cedar, H. DNA methylation in cancer and aging. Cancer Res., 2016, 76(12), 3446-3450.
[http://dx.doi.org/10.1158/0008-5472.CAN-15-3278] [PMID: 27256564]
[40]
Sromek, M.; Glogowski, M.; Chechlinska, M.; Kulinczak, M.; Szafron, L.; Zakrzewska, K.; Owczarek, J.; Wisniewski, P.; Wlodarczyk, R.; Talarek, L.; Turski, M.; Siwicki, J.K. Changes in plasma miR-9, miR-16, miR-205 and miR-486 levels after non-small cell lung cancer resection. Cell Oncol. (Dordr.), 2017, 40(5), 529-536.
[http://dx.doi.org/10.1007/s13402-017-0334-8] [PMID: 28634901]

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