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Year 2020, Volume: 41 Issue: 4, 775 - 783, 29.12.2020

Elif Burcu Bali

https://doi.org/10.17776/csj.768907

Abstract

References

  • [1] Parisi D., Adasme M.F., Sveshnikova A., Bolz S.N., Moreau Y., Schroeder M., Drug repositioning or target repositioning: A structural perspective of drug-target-indication relationship for available repurposed drugs, Comput Struct Biotechnol J., 18 (2020) 1043–1055.
  • [2] Yoon W.S., Yeom M.Y., Kang E.S., Chung Y.A., Chung D.S., Jeun S.S., Memantine Induces NMDAR1-Mediated Autophagic Cell Death in Malignant Glioma Cells, J. Korean Neurosurg. Soc., 60(2) (2017) 130-137.
  • [3] Lowinus T., Heidel F.H., Bose T., Nimmagadda S.C., Schnöder T., Cammann C., Schmitz I., Seifert U., Fischer T., Schraven B., Bommhardt U., Memantine Potentiates Cytarabine-Induced Cell Death of Acute Leukemia Correlating With Inhibition of K v 1.3 Potassium Channels, AKT and ERK1/2 Signaling, Cell Commun. Signal.,17 (1) (2019) 5. doi: 10.1186/s12964-018-0317-z.
  • [4] Amidfar M., Réus G.Z., Quevedo J., Kim Y.K., The role of memantine in the treatment of majör depressive disorder: Clinical efficacy and mechanisms of action, Eur. J. Pharmacol., 15 (827) (2018)103-111.
  • [5] Kabir M.T., Sufian M.A., Uddin M.S., Begum M.M., Akhter S., Islam A., Mathew B., Islam M.S., Amran M.S., Md Ashraf G., NMDA Receptor Antagonists: Repositioning of Memantine as a Multitargeting Agent for Alzheimer's Therapy, Curr. Pharm. Des., 25(33) (2019) 3506‐3518.
  • [6] Yu J.Y., Zhang B., Peng L., Wu C.H., Cao H., Zhong J.F., Hoffman J., Huang S.H., Repositioning of Memantine as a Potential Novel Therapeutic Agent against Meningitic E. coli-Induced Pathogenicities through Disease-Associated Alpha7 Cholinergic Pathway and RNA Sequencing-Based Transcriptome Analysis of Host Inflammatory Responses, PLoS One.,10 (5) (2015).
  • [7] Santos Souza H.F., Rocha S.C., Damasceno F.S., Rapado L.N., Pral E.M.F., Marinho C.R.F., Silber A.M., The effect of memantine, an antagonist of the NMDA glutamate receptor, in vitro and in vivo infections by Trypanosoma cruzi, PLoS Negl. Trop. Dis., 13 (9) (2019) 1-15.
  • [8] North W.G., Gao G., Memoli V.A., Pang R.H., Lynch L., Breast cancer expresses functional NMDA receptors, Breast Cancer Res Treat., 122(2) (2010) 307‐314.
  • [9] Seifabadi S., Vaseghi G., Haghjooy Javanmard Sh., Omidi E., Tajadini M.H., Zarrin B., The cytotoxic effect of memantine and its effect on cytoskeletal proteins expression in metastatic breast cancer cell line, Iran J. Basic Med. Sci., 20 (2017) 41-45.
  • [10] Yoon W.S., Yeom M.Y., Kang E.S., Chung Y.A., Chung D.S., Jeun S.S., Memantine Induces NMDAR1-Mediated Autophagic Cell Death in Malignant Glioma Cells, J. Korean Neurosurg. Soc., 60(2) (2017)130‐137.
  • [11] Albayrak G., Konac E., Dikmen A.U., Bilen C.Y., Memantine induces apoptosis and inhibits cell cycle progression in LNCaP prostate cancer cells, Hum. Exp. Toxicol., 37(9)(2018) 953‐958.
  • [12] Deutsch S.I., Tang A.H., Burket J.A., Benson A.D., NMDA receptors on the surface of cancer cells: target for chemotherapy?, Biomed. Pharmacother., 68(4) (2014) 493‐496.
  • [13] Huang S.W., Chyuan I.T., Shiue C., Yu M.C., Hsu Y.F., Hsu M.J., Lovastatin-mediated MCF-7 cancer cell death involves LKB1-AMPK-p38MAPK-p53-survivin signalling cascade, J. Cell Mol. Med., 24(2) (2020) 1822‐1836.
  • [14] Ponnusamy L., Natarajan S.R., Thangaraj K., Manoharan R., Therapeutic aspects of AMPK in breast cancer: Progress, challenges, and future directions, Biochim. Biophys Acta Rev. Cancer., 1874(1) (2020) 188379.
  • [15] Kim H.S., Kim M.J., Lim J., Yang Y., Lee M.S., Lim J.S., NDRG2 overexpression enhances glucose deprivation-mediated apoptosis in breast cancer cells via inhibition of the LKB1-AMPK pathway, Genes Cancer., 5(5-6) (2014)175-85.
  • [16] Lee S.W., Lin H.K., A new mechanism for LKB1 activation, Mol. Cell Oncol., 5(3)(2018)
  • [17] Kim I., He Y.Y., Targeting the AMP-Activated Protein Kinase for Cancer Prevention and Therapy, Front. Oncol., 15 (3) (2013) 175.
  • [18] Ural AU, Avcu F, Candir M, Guden M, Ozcan MA. In vitro synergistic cytoreductive effects of zoledronic acid and radiation on breast cancer cells, Breast Cancer Res., 2006;8: R52.
  • [19] Bali E.B., Ergin V., Rackova L., Bayraktar O., Küçükboyaci N., Karasu Ç., Olive Leaf Extracts Protect Cardiomyocytes Against 4-hydroxynonenal-induced Toxicity in Vitro: Comparison With Oleuropein, Hydroxytyrosol, and Quercetin, Planta Med., 80(12) (2014) 984-92.
  • [20] Rio D.C., Ares M. Jr., Hannon G.J., Nilsen T.W., Purification of RNA using TRIzol (TRI reagent), Cold Spring Harb. Protoc., 2010(6) 5439.
  • [21] Livak K.J., Schmittgen T.D., Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method, Methods., 25(4) (2001) 402‐408.
  • [22] Nayak V.L., Nagesh N., Ravikumar A., Bagul C., Vishnuvardhan M.V.P.S., Srinivasulu V., Kamal A., 2-aryl benzimidazole conjugate induced apoptosis in human breast cancer MCF-7 cells through caspase independent pathway, Apoptosis, 22(1) (2017) 118-134.
  • [23] Bali E.B., Açık L., Elçi P., Sarper M., Avcu F., Vural M., In vitro anti-oxidant, cytotoxic and pro-apoptotic effects of Achillea teretifolia Willd extracts on human prostate cancer cell lines, Pharmacogn. Mag., 11(Suppl 2)(2015)S308-15.
  • [24] Sigurðsson H.H., Olesen C.W., Dybboe R., Lauritzen G., Pedersen S.F., Constitutively active ErbB2 regulates cisplatin-induced cell death in breast cancer cells via pro- and antiapoptotic mechanisms, Mol. Cancer. Res., 13(1) (2015) 63‐77.
  • [25] Stallinger A., Kretschmer N., Kleinegger F., Brvar L., Liegl-Atzwanger B., Prokesch A., Durchschein C., Bauer R., Deutsch A., Rinner B., β, β-Dimethylacrylshikonin Induces Apoptosis in Melanoma Cell Lines by NOXA Upregulation, J. Nat. Prod., 83(2) (2020) 305–315.
  • [26] Cacciatore I., Fornasari E., Marinelli L., Eusepi P., Ciulla M., Ozdemir O., Tatar A., Turkez H., Di Stefano A., Memantine-derived drugs as potential antitumor agents for the treatment of glioblastoma, Eur. J. Pharm. Sci.,15 (109) (2017) 402-411.
  • [27] Shackelford D.B., Shaw R.J., The LKB1-AMPK pathway: metabolism and growth control in tumour suppression, Nat. Rev. Cancer., 9 (2009) 563–75.
  • [28] Chen I.C., Chang Y.C., Lu Y.S., Chung K.P., Huang C.S., Lu T.P., Kuo W.H., Wang M.Y., Kuo K.T., Wu P.F., Hsueh T.H., Shen C.Y., Lin C.H., Cheng A.L., Clinical Relevance of Liver Kinase B1(LKB1) Protein and Gene Expression in Breast Cancer, Sci Rep., 15(6) (2016) 21374.
  • [29] Shen Z., Xf W., Lan F., Shen Z., Zm S., The tumor suppressor gene LKB1 is associated with prognosis in human breast carcinoma, Clin. Cancer Res., 8 (2002) 2085–2090.
  • [30] Baek S.Y., Hwang U.W., Suk H.Y., Kim Y.W., Hemistepsin A Inhibits Cell Proliferation and Induces G0/G1-Phase Arrest, Cellular Senescence and Apoptosis Via the AMPK and p53/p21 Signals in Human Hepatocellular Carcinoma, Biomolecules., 10 (5) (2020) 713.
  • [31] Zhao W., Zhang X., Liu J., Sun B., Tang H., Zhang H., miR-27a-mediated antiproliferative effects of metformin on the breast cancer cell line MCF-7, Oncol Rep., 36(6) (2016) 3691-3699.
  • [32] Fox M.M., Phoenix K.N., Kopsiaftis S.G., Claffey K.P., AMP-activated protein kinase α 2 isoform suppression in primary breast cancer alters AMPK growth control and apoptotic signaling, Genes Cancer, 4 (2013) 3-14.
  • [33] Sridharan S., Basu A., Distinct Roles of mTOR Targets S6K1 and S6K2 in Breast Cancer, Int. J. Mol. Sci., 21(4) (2020) 1199.
  • [34] Perez-Tenorio G., Karlsson, E., Waltersson M.A., Olsson B., Holmlund B., Nordenskjold B., Fornander T., Skoog L., Stal O., Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer, Breast Cancer Res. Treat, 128 (2011) 713–723.
  • [35] Karlsson E., Waltersson M.A., Bostner J., Perez-Tenorio G., Olsson B., Hallbeck A.L., Stal O., High-resolution genomic analysis of the 11q13 amplicon in breast cancers identifies synergy with 8p12 amplification, involving the mTOR targets S6K2 and 4EBP1, Genes Chromosom. Cancer, 50 (2011)775–787.
  • [36] Qin X., Jiang B., Zhang Y., 4E-BP1, a multifactor regulated multifunctional protein, Cell Cycle, 15(6) (2016) 781‐786.
  • [37] Rutkovsky A.C., Yeh E.S., Guest S.T., Findlay V.J., Muise-Helmericks R.C., Armeson K., Ethier S.P., Eukaryotic initiation factor 4E-binding protein as an oncogene in breast cancer, BMC Cancer., 19 (1) (2019) 491.

Memantine activates LKB1-AMPK pathway in breast carcinoma cells

Year 2020, Volume: 41 Issue: 4, 775 - 783, 29.12.2020

Elif Burcu Bali

https://doi.org/10.17776/csj.768907

Abstract

Drug repositioning that is a screening of presently approved drugs for already unknown indications is therapeutically necessary and influential for drug discovery. In this study, it was aimed to research whether memantine as a repositioned drug can activate the LKB1-AMPK pathway in breast carcinoma cells by triggering tumor suppressor genes LKB1, AMPK, its downstream targets 40S ribosomal S6 kinases (S6K1 and S6K2), and eukaryotic initiation factor 4E-binding protein 4E-BP1. It was also evaluated its apoptotic effect by detecting the gene expressions of Caspase 7 and NOXA. Thus, MCF-7 cells were treated with 250 µM memantine for 48 h, and its cytotoxic effect was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. AMPKα1, AMPKα2, S6K1, S6K2, 4E-BP1, Caspase 7 and NOXA gene expression levels were measured by quantitative real-time polymerase chain reaction. The results clearly revealed that memantine inhibited MCF-7 cell proliferation and activated the LKB1-AMPK pathway by reducing S6K1, S6K2, and 4EBP1 gene expressions. Memantine also augmented the gene expressions of Caspase 7 and NOXA. The findings reveal a molecular mechanism for the first time that may contribute to the anti-cancer effect of memantine to prevent or treat breast cancer. But further research should be performed to better understand its anti-cancer action. 

Keywords

Memantine breast carcinoma LKB1-AMPK pathway real-time polymerase chain reaction Caspase 7

References

  • [1] Parisi D., Adasme M.F., Sveshnikova A., Bolz S.N., Moreau Y., Schroeder M., Drug repositioning or target repositioning: A structural perspective of drug-target-indication relationship for available repurposed drugs, Comput Struct Biotechnol J., 18 (2020) 1043–1055.
  • [2] Yoon W.S., Yeom M.Y., Kang E.S., Chung Y.A., Chung D.S., Jeun S.S., Memantine Induces NMDAR1-Mediated Autophagic Cell Death in Malignant Glioma Cells, J. Korean Neurosurg. Soc., 60(2) (2017) 130-137.
  • [3] Lowinus T., Heidel F.H., Bose T., Nimmagadda S.C., Schnöder T., Cammann C., Schmitz I., Seifert U., Fischer T., Schraven B., Bommhardt U., Memantine Potentiates Cytarabine-Induced Cell Death of Acute Leukemia Correlating With Inhibition of K v 1.3 Potassium Channels, AKT and ERK1/2 Signaling, Cell Commun. Signal.,17 (1) (2019) 5. doi: 10.1186/s12964-018-0317-z.
  • [4] Amidfar M., Réus G.Z., Quevedo J., Kim Y.K., The role of memantine in the treatment of majör depressive disorder: Clinical efficacy and mechanisms of action, Eur. J. Pharmacol., 15 (827) (2018)103-111.
  • [5] Kabir M.T., Sufian M.A., Uddin M.S., Begum M.M., Akhter S., Islam A., Mathew B., Islam M.S., Amran M.S., Md Ashraf G., NMDA Receptor Antagonists: Repositioning of Memantine as a Multitargeting Agent for Alzheimer's Therapy, Curr. Pharm. Des., 25(33) (2019) 3506‐3518.
  • [6] Yu J.Y., Zhang B., Peng L., Wu C.H., Cao H., Zhong J.F., Hoffman J., Huang S.H., Repositioning of Memantine as a Potential Novel Therapeutic Agent against Meningitic E. coli-Induced Pathogenicities through Disease-Associated Alpha7 Cholinergic Pathway and RNA Sequencing-Based Transcriptome Analysis of Host Inflammatory Responses, PLoS One.,10 (5) (2015).
  • [7] Santos Souza H.F., Rocha S.C., Damasceno F.S., Rapado L.N., Pral E.M.F., Marinho C.R.F., Silber A.M., The effect of memantine, an antagonist of the NMDA glutamate receptor, in vitro and in vivo infections by Trypanosoma cruzi, PLoS Negl. Trop. Dis., 13 (9) (2019) 1-15.
  • [8] North W.G., Gao G., Memoli V.A., Pang R.H., Lynch L., Breast cancer expresses functional NMDA receptors, Breast Cancer Res Treat., 122(2) (2010) 307‐314.
  • [9] Seifabadi S., Vaseghi G., Haghjooy Javanmard Sh., Omidi E., Tajadini M.H., Zarrin B., The cytotoxic effect of memantine and its effect on cytoskeletal proteins expression in metastatic breast cancer cell line, Iran J. Basic Med. Sci., 20 (2017) 41-45.
  • [10] Yoon W.S., Yeom M.Y., Kang E.S., Chung Y.A., Chung D.S., Jeun S.S., Memantine Induces NMDAR1-Mediated Autophagic Cell Death in Malignant Glioma Cells, J. Korean Neurosurg. Soc., 60(2) (2017)130‐137.
  • [11] Albayrak G., Konac E., Dikmen A.U., Bilen C.Y., Memantine induces apoptosis and inhibits cell cycle progression in LNCaP prostate cancer cells, Hum. Exp. Toxicol., 37(9)(2018) 953‐958.
  • [12] Deutsch S.I., Tang A.H., Burket J.A., Benson A.D., NMDA receptors on the surface of cancer cells: target for chemotherapy?, Biomed. Pharmacother., 68(4) (2014) 493‐496.
  • [13] Huang S.W., Chyuan I.T., Shiue C., Yu M.C., Hsu Y.F., Hsu M.J., Lovastatin-mediated MCF-7 cancer cell death involves LKB1-AMPK-p38MAPK-p53-survivin signalling cascade, J. Cell Mol. Med., 24(2) (2020) 1822‐1836.
  • [14] Ponnusamy L., Natarajan S.R., Thangaraj K., Manoharan R., Therapeutic aspects of AMPK in breast cancer: Progress, challenges, and future directions, Biochim. Biophys Acta Rev. Cancer., 1874(1) (2020) 188379.
  • [15] Kim H.S., Kim M.J., Lim J., Yang Y., Lee M.S., Lim J.S., NDRG2 overexpression enhances glucose deprivation-mediated apoptosis in breast cancer cells via inhibition of the LKB1-AMPK pathway, Genes Cancer., 5(5-6) (2014)175-85.
  • [16] Lee S.W., Lin H.K., A new mechanism for LKB1 activation, Mol. Cell Oncol., 5(3)(2018)
  • [17] Kim I., He Y.Y., Targeting the AMP-Activated Protein Kinase for Cancer Prevention and Therapy, Front. Oncol., 15 (3) (2013) 175.
  • [18] Ural AU, Avcu F, Candir M, Guden M, Ozcan MA. In vitro synergistic cytoreductive effects of zoledronic acid and radiation on breast cancer cells, Breast Cancer Res., 2006;8: R52.
  • [19] Bali E.B., Ergin V., Rackova L., Bayraktar O., Küçükboyaci N., Karasu Ç., Olive Leaf Extracts Protect Cardiomyocytes Against 4-hydroxynonenal-induced Toxicity in Vitro: Comparison With Oleuropein, Hydroxytyrosol, and Quercetin, Planta Med., 80(12) (2014) 984-92.
  • [20] Rio D.C., Ares M. Jr., Hannon G.J., Nilsen T.W., Purification of RNA using TRIzol (TRI reagent), Cold Spring Harb. Protoc., 2010(6) 5439.
  • [21] Livak K.J., Schmittgen T.D., Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method, Methods., 25(4) (2001) 402‐408.
  • [22] Nayak V.L., Nagesh N., Ravikumar A., Bagul C., Vishnuvardhan M.V.P.S., Srinivasulu V., Kamal A., 2-aryl benzimidazole conjugate induced apoptosis in human breast cancer MCF-7 cells through caspase independent pathway, Apoptosis, 22(1) (2017) 118-134.
  • [23] Bali E.B., Açık L., Elçi P., Sarper M., Avcu F., Vural M., In vitro anti-oxidant, cytotoxic and pro-apoptotic effects of Achillea teretifolia Willd extracts on human prostate cancer cell lines, Pharmacogn. Mag., 11(Suppl 2)(2015)S308-15.
  • [24] Sigurðsson H.H., Olesen C.W., Dybboe R., Lauritzen G., Pedersen S.F., Constitutively active ErbB2 regulates cisplatin-induced cell death in breast cancer cells via pro- and antiapoptotic mechanisms, Mol. Cancer. Res., 13(1) (2015) 63‐77.
  • [25] Stallinger A., Kretschmer N., Kleinegger F., Brvar L., Liegl-Atzwanger B., Prokesch A., Durchschein C., Bauer R., Deutsch A., Rinner B., β, β-Dimethylacrylshikonin Induces Apoptosis in Melanoma Cell Lines by NOXA Upregulation, J. Nat. Prod., 83(2) (2020) 305–315.
  • [26] Cacciatore I., Fornasari E., Marinelli L., Eusepi P., Ciulla M., Ozdemir O., Tatar A., Turkez H., Di Stefano A., Memantine-derived drugs as potential antitumor agents for the treatment of glioblastoma, Eur. J. Pharm. Sci.,15 (109) (2017) 402-411.
  • [27] Shackelford D.B., Shaw R.J., The LKB1-AMPK pathway: metabolism and growth control in tumour suppression, Nat. Rev. Cancer., 9 (2009) 563–75.
  • [28] Chen I.C., Chang Y.C., Lu Y.S., Chung K.P., Huang C.S., Lu T.P., Kuo W.H., Wang M.Y., Kuo K.T., Wu P.F., Hsueh T.H., Shen C.Y., Lin C.H., Cheng A.L., Clinical Relevance of Liver Kinase B1(LKB1) Protein and Gene Expression in Breast Cancer, Sci Rep., 15(6) (2016) 21374.
  • [29] Shen Z., Xf W., Lan F., Shen Z., Zm S., The tumor suppressor gene LKB1 is associated with prognosis in human breast carcinoma, Clin. Cancer Res., 8 (2002) 2085–2090.
  • [30] Baek S.Y., Hwang U.W., Suk H.Y., Kim Y.W., Hemistepsin A Inhibits Cell Proliferation and Induces G0/G1-Phase Arrest, Cellular Senescence and Apoptosis Via the AMPK and p53/p21 Signals in Human Hepatocellular Carcinoma, Biomolecules., 10 (5) (2020) 713.
  • [31] Zhao W., Zhang X., Liu J., Sun B., Tang H., Zhang H., miR-27a-mediated antiproliferative effects of metformin on the breast cancer cell line MCF-7, Oncol Rep., 36(6) (2016) 3691-3699.
  • [32] Fox M.M., Phoenix K.N., Kopsiaftis S.G., Claffey K.P., AMP-activated protein kinase α 2 isoform suppression in primary breast cancer alters AMPK growth control and apoptotic signaling, Genes Cancer, 4 (2013) 3-14.
  • [33] Sridharan S., Basu A., Distinct Roles of mTOR Targets S6K1 and S6K2 in Breast Cancer, Int. J. Mol. Sci., 21(4) (2020) 1199.
  • [34] Perez-Tenorio G., Karlsson, E., Waltersson M.A., Olsson B., Holmlund B., Nordenskjold B., Fornander T., Skoog L., Stal O., Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer, Breast Cancer Res. Treat, 128 (2011) 713–723.
  • [35] Karlsson E., Waltersson M.A., Bostner J., Perez-Tenorio G., Olsson B., Hallbeck A.L., Stal O., High-resolution genomic analysis of the 11q13 amplicon in breast cancers identifies synergy with 8p12 amplification, involving the mTOR targets S6K2 and 4EBP1, Genes Chromosom. Cancer, 50 (2011)775–787.
  • [36] Qin X., Jiang B., Zhang Y., 4E-BP1, a multifactor regulated multifunctional protein, Cell Cycle, 15(6) (2016) 781‐786.
  • [37] Rutkovsky A.C., Yeh E.S., Guest S.T., Findlay V.J., Muise-Helmericks R.C., Armeson K., Ethier S.P., Eukaryotic initiation factor 4E-binding protein as an oncogene in breast cancer, BMC Cancer., 19 (1) (2019) 491.
There are 37 citations in total.

Details

Primary Language English
Subjects Structural Biology
Journal Section Natural Sciences
Authors

Elif Burcu Bali 0000-0002-8797-0573

Publication Date December 29, 2020
Submission Date July 13, 2020
Acceptance Date November 3, 2020
Published in Issue Year 2020Volume: 41 Issue: 4

Cite

APA Bali, E. B. (2020). Memantine activates LKB1-AMPK pathway in breast carcinoma cells. Cumhuriyet Science Journal, 41(4), 775-783. https://doi.org/10.17776/csj.768907