Login Register Cart 0
Combinatorial Chemistry & High Throughput Screening

Combinatorial Chemistry & High Throughput Screening

Editor-in-Chief

ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

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

LincRNA-p21 Promotes Cellular Senescence by Down-regulating the Wnt/β-catenin Pathway in MPP+-treated SH-SY5Y Cells

Author(s): Jianyu Zhu and Lingli Chen*

Volume 26, Issue 14, 2023

Published on: 10 May, 2023

Page: [2476 - 2486] Pages: 11

DOI: 10.2174/1386207326666230417103137

open_access

Become a Editorial Board Member
Become a Reviewer
Become a Editor
Become a Section Editor

Abstract

Aim and Objective: Long intergenic non-coding RNA-p21 (lincRNA-p21) plays a critical role in various senescence-associated physiological and pathological conditions. We aimed to explore the senescence-associated effects of lincRNA-p21 in 1-methyl-4-phenylpyridinium (MPP+) treated neuroblastoma SH-SY5Y cell line as a therapeutic target.

Materials and Methods: The RNA expression levels of lincRNA-p21, p53, p16, and telomere length were examined with reverse transcription-quantitative polymerase chain reaction (RTqPCR). The Telo TAGGG™ Telomerase PCR ELISA PLUS Kit was used to determine telomerase activity. Cellular viability was evaluated with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and lactate dehydrogenase (LDH) assay. Western blot was performed to analyze β-catenin protein expression. Besides, oxidative stress was evaluated by Jaggregate- forming delocalized lipophilic cation, 5,5',6,6'-tetrachloro-1,1',3,3'- tetraethylbenzimidazolocarbocyanine++ + iodide (JC‑1) stain, fluorescence spectrophotometry, colorimetric assay, and malondialdehyde (MDA) formation.

Results: This research demonstrated that MPP+ caused a distinct increase in the expression of LincRNA- p21 in SH-SY5Y cells. MPP+ induced cellular senescence with decreasing cellular proliferation and viability, increasing expression levels of senescence-associated makers such as genes p53 and p16, accompanied by significantly decreasing telomere length and telomerase activity. At the same time, these effects were abolished by silencing lincRNA-p21 with small interfering RNA (siRNA). On the contrary, β-catenin silencing contributes to reversing anti-senescent effects caused by lincRNA-p21 silencing. Moreover, modifying lincRNA-p21 exerted an anti-senescent influence depending on decreasing oxidant stress.

Conclusion: Our study showed that in the treatment of MPP+, lincRNA-p21 might serve a role in the SH-SY5Y cell senescence by modulating the Wnt/β-catenin pathway, as well as increasing oxidant stress. Thus, trying to target lincRNA-p21 may have important therapeutic and practical implications for PD.

Keywords: Lincrna-p21, senescence, Wnt/β catenin pathway, 1-methyl-4-phenylpyridinium, SH-SY5Y, DAT.

« Previous Next »
[1]
Bloem, B.R.; Okun, M.S.; Klein, C. Parkinson’s disease. Lancet, 2021, 397(10291), 2284-2303.
[http://dx.doi.org/10.1016/S0140-6736(21)00218-X] [PMID: 33848468]
[2]
Dauer, W.; Przedborski, S. Parkinson’s Disease. Neuron, 2003, 39(6), 889-909.
[http://dx.doi.org/10.1016/S0896-6273(03)00568-3] [PMID: 12971891]
[3]
Koller, W.C.; Rueda, M.G. Mechanism of action of dopaminergic agents in Parkinson’s disease. Neurology, 1998, 50(Suppl. 6), S11-S14.
[http://dx.doi.org/10.1212/WNL.50.6_Suppl_6.S11] [PMID: 9633680]
[4]
Jenner, P. Oxidative stress in Parkinson’s disease. Ann. Neurol., 2003, 53(S3), S26-S38.
[http://dx.doi.org/10.1002/ana.10483] [PMID: 12666096]
[5]
Chen, C.; Turnbull, D.M.; Reeve, A.K. Mitochondrial dysfunction in Parkinson’s disease—cause or consequence? Biology, 2019, 8(2), 38.
[http://dx.doi.org/10.3390/biology8020038] [PMID: 31083583]
[6]
Asghar, M.; Odeh, A.; Fattahi, A.J.; Henriksson, A.E.; Miglar, A.; Khosousi, S.; Svenningsson, P. Mitochondrial biogenesis, telomere length and cellular senescence in Parkinson’s disease and Lewy body dementia. Sci. Rep., 2022, 12(1), 17578.
[http://dx.doi.org/10.1038/s41598-022-22400-z] [PMID: 36266468]
[7]
Luo, Q.; Sun, W.; Wang, Y.F.; Li, J.; Li, D.W. Association of p53 with neurodegeneration in Parkinson’s disease. Parkinsons Dis., 2022, 2022, 1-11.
[http://dx.doi.org/10.1155/2022/6600944] [PMID: 35601652]
[8]
Ferrer, I.; Martinez, A.; Blanco, R.; Dalfó, E.; Carmona, M. Neuropathology of sporadic Parkinson disease before the appearance of parkinsonism: Preclinical Parkinson disease. J. Neural Transm., 2011, 118(5), 821-839.
[http://dx.doi.org/10.1007/s00702-010-0482-8] [PMID: 20862500]
[9]
Trist, B.G.; Hare, D.J.; Double, K.L. Oxidative stress in the aging substantia nigra and the etiology of Parkinson’s disease. Aging Cell, 2019, 18(6), e13031.
[http://dx.doi.org/10.1111/acel.13031] [PMID: 31432604]
[10]
Anik, M.I.; Mahmud, N.; Masud, A.A.; Khan, M.I.; Islam, M.N.; Uddin, S.; Hossain, M.K. Role of reactive oxygen species in aging and age-related diseases: A review. ACS Appl. Bio Mater., 2022, acsabm.2c00411.
[http://dx.doi.org/10.1021/acsabm.2c00411] [PMID: 36043942]
[11]
Chen, Z.; Rasheed, M.; Deng, Y. The epigenetic mechanisms involved in mitochondrial dysfunction: Implication for Parkinson’s disease. Brain Pathol., 2022, 32(3), e13012.
[http://dx.doi.org/10.1111/bpa.13012] [PMID: 34414627]
[12]
Chakravarti, D.; LaBella, K.A.; DePinho, R.A. Telomeres: History, health, and hallmarks of aging. Cell, 2021, 184(2), 306-322.
[http://dx.doi.org/10.1016/j.cell.2020.12.028] [PMID: 33450206]
[13]
Allsopp, R. Take a ride on the telomere-aging train. J. Gerontol. A Biol. Sci. Med. Sci., 2021, 76(1), 1-2.
[http://dx.doi.org/10.1093/gerona/glaa245] [PMID: 33355657]
[14]
Schwab, A.D.; Thurston, M.J.; Machhi, J.; Olson, K.E.; Namminga, K.L.; Gendelman, H.E.; Mosley, R.L. Immunotherapy for Parkinson’s disease. Neurobiol. Dis., 2020, 137, 104760.
[http://dx.doi.org/10.1016/j.nbd.2020.104760] [PMID: 31978602]
[15]
Tang, S.S.; Zheng, B.Y.; Xiong, X.D. LincRNA-p21: Implications in human diseases. Int. J. Mol. Sci., 2015, 16(8), 18732-18740.
[http://dx.doi.org/10.3390/ijms160818732] [PMID: 26270659]
[16]
Jin, S.; Yang, X.; Li, J.; Yang, W.; Ma, H.; Zhang, Z. p53-targeted lincRNA-p21 acts as a tumor suppressor by inhibiting JAK2/STAT3 signaling pathways in head and neck squamous cell carcinoma. Mol. Cancer, 2019, 18(1), 38.
[http://dx.doi.org/10.1186/s12943-019-0993-3] [PMID: 30857539]
[17]
Chen, S.; Liang, H.; Yang, H.; Zhou, K.; Xu, L.; Liu, J.; Lai, B.; Song, L.; Luo, H.; Peng, J.; Liu, Z.; Xiao, Y.; Chen, W.; Tang, H. LincRNa-p21: function and mechanism in cancer. Med. Oncol., 2017, 34(5), 98.
[http://dx.doi.org/10.1007/s12032-017-0959-5] [PMID: 28425074]
[18]
Kraus, T.F.J.; Haider, M.; Spanner, J.; Steinmaurer, M.; Dietinger, V.; Kretzschmar, H.A. Altered long noncoding rna expression precedes the course of Parkinson’s disease-A preliminary report. Mol. Neurobiol., 2017, 54(4), 2869-2877.
[http://dx.doi.org/10.1007/s12035-016-9854-x] [PMID: 27021022]
[19]
Chen, Y.; Li, Z.; Chen, X.; Zhang, S. Long non-coding RNAs: From disease code to drug role. Acta Pharm. Sin. B, 2021, 11(2), 340-354.
[http://dx.doi.org/10.1016/j.apsb.2020.10.001] [PMID: 33643816]
[20]
Yu, F.; Guo, Y.; Chen, B.; Shi, L.; Dong, P.; Zhou, M.; Zheng, J. LincRNA-p21 inhibits the Wnt/β-catenin pathway in activated hepatic stellate cells via sponging MicroRNA-17-5p. Cell. Physiol. Biochem., 2017, 41(5), 1970-1980.
[http://dx.doi.org/10.1159/000472410] [PMID: 28391277]
[21]
Xia, W.; Zhuang, L.; Deng, X.; Hou, M. Long noncoding RNA-p21 modulates cellular senescence via the Wnt/β-catenin signaling pathway in mesenchymal stem cells. Mol. Med. Rep., 2017, 16(5), 7039-7047.
[http://dx.doi.org/10.3892/mmr.2017.7430] [PMID: 28901439]
[22]
Nusse, R.; Clevers, H. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell, 2017, 169(6), 985-999.
[http://dx.doi.org/10.1016/j.cell.2017.05.016] [PMID: 28575679]
[23]
Liu, J.; Xiao, Q.; Xiao, J.; Niu, C.; Li, Y.; Zhang, X.; Zhou, Z.; Shu, G.; Yin, G. Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct. Target. Ther., 2022, 7(1), 3.
[http://dx.doi.org/10.1038/s41392-021-00762-6] [PMID: 34980884]
[24]
Marchetti, B.; Tirolo, C.; L’Episcopo, F.; Caniglia, S.; Testa, N.; Smith, J.A.; Pluchino, S.; Serapide, M.F. Parkinson’s disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair. Aging Cell, 2020, 19(3), e13101.
[http://dx.doi.org/10.1111/acel.13101] [PMID: 32050297]
[25]
Jakaria, M.; Park, S.Y.; Haque, M.E.; Karthivashan, G.; Kim, I.S.; Ganesan, P.; Choi, D.K. Neurotoxic agent-induced injury in neurodegenerative disease model: Focus on involvement of glutamate receptors. Front. Mol. Neurosci., 2018, 11, 307.
[http://dx.doi.org/10.3389/fnmol.2018.00307] [PMID: 30210294]
[26]
Langston, J.W.; Ballard, P.; Tetrud, J.W.; Irwin, I. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science, 1983, 219(4587), 979-980.
[http://dx.doi.org/10.1126/science.6823561] [PMID: 6823561]
[27]
Feng, Z.; Zhang, L.; Wang, S.; Hong, Q. Circular RNA circDLGAP4 exerts neuroprotective effects via modulating miR-134-5p/CREB pathway in Parkinson’s disease. Biochem. Biophys. Res. Commun., 2020, 522(2), 388-394.
[http://dx.doi.org/10.1016/j.bbrc.2019.11.102] [PMID: 31761328]
[28]
Crepin, T.; Carron, C.; Roubiou, C.; Gaugler, B.; Gaiffe, E.; Simula-Faivre, D.; Ferrand, C.; Tiberghien, P.; Chalopin, J.M.; Moulin, B.; Frimat, L.; Rieu, P.; Saas, P.; Ducloux, D.; Bamoulid, J. ATG-induced accelerated immune senescence: Clinical implications in renal transplant recipients. Am. J. Transplant., 2015, 15(4), 1028-1038.
[http://dx.doi.org/10.1111/ajt.13092] [PMID: 25758660]
[29]
Vallée, A.; Vallée, J.N.; Lecarpentier, Y. Potential role of cannabidiol in Parkinson’s disease by targeting the WNT/β-catenin pathway, oxidative stress and inflammation. Aging, 2021, 13(7), 10796-10813.
[http://dx.doi.org/10.18632/aging.202951] [PMID: 33848261]
[30]
Chen, L.; Yuan, D.; Yang, Y.; Ren, M. LincRNA‐p21 enhances the sensitivity of radiotherapy for gastric cancer by targeting the β‐catenin signaling pathway. J. Cell. Biochem., 2019, 120(4), 6178-6187.
[http://dx.doi.org/10.1002/jcb.27905] [PMID: 30484893]
[31]
Si, Z.; Sun, L.; Wang, X. Evidence and perspectives of cell senescence in neurodegenerative diseases. Biomed. Pharmacother., 2021, 137, 111327.
[http://dx.doi.org/10.1016/j.biopha.2021.111327] [PMID: 33545662]
[32]
Wei, L.; Sun, C.; Lei, M.; Li, G.; Yi, L.; Luo, F.; Li, Y.; Ding, L.; Liu, Z.; Li, S.; Xu, P. Activation of Wnt/β-catenin pathway by exogenous Wnt1 protects SH-SY5Y cells against 6-hydroxydopamine toxicity. J. Mol. Neurosci., 2013, 49(1), 105-115.
[http://dx.doi.org/10.1007/s12031-012-9900-8] [PMID: 23065334]
[33]
Liu, Y.; Hao, S.; Yang, B.; Fan, Y.; Qin, X.; Chen, Y.; Hu, J. Wnt/β-catenin signaling plays an essential role in α7 nicotinic receptor-mediated neuroprotection of dopaminergic neurons in a mouse Parkinson’s disease model. Biochem. Pharmacol., 2017, 140, 115-123.
[http://dx.doi.org/10.1016/j.bcp.2017.05.017] [PMID: 28551099]
[34]
Wang, Q.; Liu, Y. Cryptotanshinone ameliorates MPP+-induced oxidative stress and apoptosis of SH-SY5Y neuroblastoma cells: the role of STAT3 in Parkinson’s disease. Metab. Brain Dis., 2022, 37(5), 1477-1485.
[http://dx.doi.org/10.1007/s11011-022-00905-w] [PMID: 35396628]
[35]
Xu, X.; Zhuang, C.; Wu, Z.; Qiu, H.; Feng, H.; Wu, J. LincRNA-p21 inhibits cell viability and promotes cell apoptosis in parkinson’s disease through activating α -Synuclein expression. BioMed Res. Int., 2018, 2018, 1-10.
[http://dx.doi.org/10.1155/2018/8181374] [PMID: 30671473]
[36]
Tabassum, R.; Jeong, N.Y. Potential for therapeutic use of hydrogen sulfide in oxidative stress-induced neurodegenerative diseases. Int. J. Med. Sci., 2019, 16(10), 1386-1396.
[http://dx.doi.org/10.7150/ijms.36516] [PMID: 31692944]
[37]
Vallée, A.; Vallée, J.N.; Lecarpentier, Y. Parkinson’s disease: Potential actions of lithium by targeting the WNT/β-catenin pathway, oxidative stress, inflammation and glutamatergic pathway. Cells, 2021, 10(2), 230.
[http://dx.doi.org/10.3390/cells10020230] [PMID: 33503974]
[38]
Serafino, A.; Cozzolino, M. The Wnt/β-catenin signaling: A multifunctional target for neuroprotective and regenerative strategies in Parkinson’s disease. Neural Regen. Res., 2023, 18(2), 306-308.
[http://dx.doi.org/10.4103/1673-5374.343908] [PMID: 35900408]

Rights & Permissions Print Cite
Article Metrics
Pdf icon 42
Html icon 2
Find your institution