Login Register Cart 0
Generic placeholder image

当代肿瘤药物靶点

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 English
Research Article

人胃癌MeCP2通过促进PDK-1转录激活AKT通路增加顺铂耐药

卷 22, 期 5, 2022

发表于: 22 April, 2022

页: [414 - 425] 页: 12

弟呕挨: 10.2174/1568009622666220223115216

价格: $65

摘要

背景:越来越多的证据表明致癌基因失衡与癌症化疗耐药有关。甲基-CpG-结合蛋白2 （Methyl-CpG binding protein 2, MeCP2）是多种基因表达的主要表观调控因子，参与胃癌的发生发展过程。然而，MeCP2在胃癌获得性顺铂耐药中是否起重要作用尚不清楚。 目的:研究抑制MeCP2表达是否能使DDP耐药GC细胞对DDP敏感，并阐明其分子机制。 方法:采用qRT-PCR和免疫印迹法检测MeCP2在DDP耐药GC细胞中的表达。随后，通过细胞活力、集落形成、细胞周期、凋亡和致瘤性实验来探讨MeCP2的体内外作用。采用染色质免疫沉淀- qPCR和荧光素酶报告基因检测3-磷酸肌苷依赖性蛋白激酶1 （PDK-1）是否为MeCP2的直接靶基因。 结果:与非DDP耐药GC细胞或正常胃上皮细胞相比，恶性DDP耐药细胞MeCP2表达上调。MeCP2基因低表达增加了DDP耐药GC细胞对DDP的敏感性，导致细胞生长减慢，G0/G1期阻滞，凋亡增加，而MeCP2过表达降低了DDP耐药GC细胞对DDP的敏感性。此外，MeCP2基因的下调也增强了DDP在体内的敏感性。MeCP2通过与启动子区CpG位点结合提高PDK-1的表达，抑制PDK-1可逆转MeCP2过表达对GC细胞DDP耐药的诱导作用。 结论:这些结果表明，沉默MeCP2可能会增强DDP诱导的细胞死亡，从而为胃癌提供一种有前景的治疗策略。

关键词: 化疗耐药、顺铂、MeCP2、PDK-1、胃癌、DDP敏感性。

« Previous Next »
图形摘要

[1]
Torre, L.A.; Bray, F.; Siegel, R.L.; Ferlay, J.; Lortet-Tieulent, J.; Jemal, A. Global cancer statistics, 2012. CA Cancer J. Clin., 2015, 65(2), 87-108.
[http://dx.doi.org/10.3322/caac.21262] [PMID: 25651787]
[2]
Tan, P.; Yeoh, K.G. Genetics and molecular pathogenesis of gastric adenocarcinoma. Gastroenterology, 2015, 149(5), 1153-1162.e3.
[http://dx.doi.org/10.1053/j.gastro.2015.05.059] [PMID: 26073375]
[3]
Sakuramoto, S.; Sasako, M.; Yamaguchi, T.; Kinoshita, T.; Fujii, M.; Nashimoto, A.; Furukawa, H.; Nakajima, T.; Ohashi, Y.; Imamura, H.; Higashino, M.; Yamamura, Y.; Kurita, A.; Arai, K. ACTS-GC Group. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N. Engl. J. Med., 2007, 357(18), 1810-1820.
[http://dx.doi.org/10.1056/NEJMoa072252] [PMID: 17978289]
[4]
Verstraelen, J.; Reichl, S. Multidrug resistance-associated protein (MRP1, 2, 4 and 5) expression in human corneal cell culture models and animal corneal tissue. Mol. Pharm., 2014, 11(7), 2160-2171.
[http://dx.doi.org/10.1021/mp400625z] [PMID: 24456047]
[5]
Greger, J.G.; Eastman, S.D.; Zhang, V.; Bleam, M.R.; Hughes, A.M.; Smitheman, K.N.; Dickerson, S.H.; Laquerre, S.G.; Liu, L.; Gilmer, T.M. Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations. Mol. Cancer Ther., 2012, 11(4), 909-920.
[http://dx.doi.org/10.1158/1535-7163.MCT-11-0989] [PMID: 22389471]
[6]
Bachleitner-Hofmann, T.; Sun, M.Y.; Chen, C.T.; Tang, L.; Song, L.; Zeng, Z.; Shah, M.; Christensen, J.G.; Rosen, N.; Solit, D.B.; Weiser, M.R. HER kinase activation confers resistance to MET tyrosine kinase inhibition in MET oncogene-addicted gastric cancer cells. Mol. Cancer Ther., 2008, 7(11), 3499-3508.
[http://dx.doi.org/10.1158/1535-7163.MCT-08-0374] [PMID: 18974395]
[7]
Chen, C.T.; Kim, H.; Liska, D.; Gao, S.; Christensen, J.G.; Weiser, M.R. MET activation mediates resistance to lapatinib inhibition of HER2-amplified gastric cancer cells. Mol. Cancer Ther., 2012, 11(3), 660-669.
[http://dx.doi.org/10.1158/1535-7163.MCT-11-0754] [PMID: 22238368]
[8]
Hite, K.C.; Adams, V.H. Hansen, JC Recent advances in MeCP2 structure and function. Biochem. Cell Biol., 2009, 87(1), 219-227.
[9]
Yasui, D.H.; Peddada, S.; Bieda, M.C.; Vallero, R.O.; Hogart, A.; Nagarajan, R.P.; Thatcher, K.N.; Farnham, P.J.; Lasalle, J.M. Integrated epigenomic analyses of neuronal MeCP2 reveal a role for long-range interaction with active genes. Proc. Natl. Acad. Sci. USA, 2007, 104(49), 19416-19421.
[http://dx.doi.org/10.1073/pnas.0707442104] [PMID: 18042715]
[10]
Chahrour, M.; Jung, S.Y.; Shaw, C.; Zhou, X.; Wong, S.T.C.; Qin, J.; Zoghbi, H.Y. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science, 2008, 320(5880), 1224-1229.
[http://dx.doi.org/10.1126/science.1153252] [PMID: 18511691]
[11]
Mellén, M.; Ayata, P.; Dewell, S.; Kriaucionis, S.; Heintz, N. MeCP2 binds to 5hmC enriched within active genes and accessible chromatin in the nervous system. Cell, 2012, 151(7), 1417-1430.
[http://dx.doi.org/10.1016/j.cell.2012.11.022] [PMID: 23260135]
[12]
Darwanto, A.; Kitazawa, R.; Maeda, S.; Kitazawa, S. MeCP2 and promoter methylation cooperatively regulate E-cadherin gene expression in colorectal carcinoma. Cancer Sci., 2003, 94(5), 442-447.
[http://dx.doi.org/10.1111/j.1349-7006.2003.tb01462.x] [PMID: 12824891]
[13]
Joss-Moore, L.A.; Wang, Y.; Ogata, E.M.; Sainz, A.J.; Yu, X.; Callaway, C.W.; McKnight, R.A.; Albertine, K.H.; Lane, R.H. IUGR differentially alters MeCP2 expression and H3K9Me3 of the PPARγ gene in male and female rat lungs during alveolarization. Birth Defects Res. A Clin. Mol. Teratol., 2011, 91(8), 672-681.
[http://dx.doi.org/10.1002/bdra.20783] [PMID: 21425435]
[14]
Bernard, D.; Gil, J.; Dumont, P.; Rizzo, S.; Monté, D.; Quatannens, B.; Hudson, D.; Visakorpi, T.; Fuks, F.; de Launoit, Y. The methyl-CpG-binding protein MECP2 is required for prostate cancer cell growth. Oncogene, 2006, 25(9), 1358-1366.
[http://dx.doi.org/10.1038/sj.onc.1209179] [PMID: 16331274]
[15]
Tong, D.; Zhang, J.; Wang, X.; Li, Q.; Liu, L.Y.; Yang, J.; Guo, B.; Ni, L.; Zhao, L.; Huang, C. MeCP2 facilitates breast cancer growth via promoting ubiquitination-mediated P53 degradation by inhibiting RPL5/RPL11 transcription. Oncogenesis, 2020, 9(5), 56.
[http://dx.doi.org/10.1038/s41389-020-0239-7] [PMID: 32483207]
[16]
Danam, R.P.; Howell, S.R.; Brent, T.P.; Harris, L.C. Epigenetic regulation of O6-methylguanine-DNA methyltransferase gene expression by histone acetylation and methyl-CpG binding proteins. Mol. Cancer Ther., 2005, 4(1), 61-69.
[PMID: 15657354]
[17]
Zhao, L.; Liu, Y.; Tong, D.; Qin, Y.; Yang, J.; Xue, M.; Du, N.; Liu, L.; Guo, B.; Hou, N.; Han, J.; Liu, S.; Liu, N.; Zhao, X.; Wang, L.; Chen, Y.; Huang, C. MeCP2 promotes gastric cancer progression through regulating foxf1/wnt5a/β-catenin and myod1/caspase-3 signaling pathways. EBioMedicine, 2017, 16, 87-100.
[http://dx.doi.org/10.1016/j.ebiom.2017.01.021] [PMID: 28131747]
[18]
Cavazzuti, M.; Duffy, T.E. C-JUN regulates PDK1 transcription: Implication for AKT and PKC activities and melanoma tumorigenesis. J. Biol. Chem., 2009, 285(2), 903.
[PMID: 19910471]
[19]
Iorns, E.; Lord, C.J.; Ashworth, A. Parallel RNAi and compound screens identify the PDK1 pathway as a target for tamoxifen sensitization. Biochem. J., 2009, 417(1), 361-370.
[http://dx.doi.org/10.1042/BJ20081682] [PMID: 18976239]
[20]
Kasowski, M.; Grubert, F.; Heffelfinger, C.; Hariharan, M.; Asabere, A.; Waszak, S.M.; Habegger, L.; Rozowsky, J.; Shi, M.; Urban, A.E.; Hong, M.Y.; Karczewski, K.J.; Huber, W.; Weissman, S.M.; Gerstein, M.B.; Korbel, J.O.; Snyder, M. Variation in transcription factor binding among humans. Science, 2010, 328(5975), 232-235.
[http://dx.doi.org/10.1126/science.1183621] [PMID: 20299548]
[21]
Zhao, L.Y.; Tong, D.D.; Xue, M.; Ma, H.L.; Liu, S.Y.; Yang, J.; Liu, Y.X.; Guo, B.; Ni, L.; Liu, L.Y.; Qin, Y.N.; Wang, L.M.; Zhao, X.G.; Huang, C. MeCP2, a target of miR-638, facilitates gastric cancer cell proliferation through activation of the MEK1/2-ERK1/2 signaling pathway by upregulating GIT1. Oncogenesis, 2017, 6(7), e368.
[http://dx.doi.org/10.1038/oncsis.2017.60] [PMID: 28759023]
[22]
Sun, X.P.; Dong, X.; Lin, L.; Jiang, X.; Wei, Z.; Zhai, B.; Sun, B.; Zhang, Q.; Wang, X.; Jiang, H.; Krissansen, G.W.; Qiao, H.; Sun, X. Up-regulation of survivin by AKT and hypoxia-inducible factor 1α contributes to cisplatin resistance in gastric cancer. FEBS J., 2014, 281(1), 115-128.
[http://dx.doi.org/10.1111/febs.12577] [PMID: 24165223]
[23]
Du, Y.; Zhu, M.; Zhou, X.; Huang, Z.; Zhu, J.; Xu, J.; Cheng, G.; Shu, Y.; Liu, P.; Zhu, W.; Wang, T. miR-20a enhances cisplatin resistance of human gastric cancer cell line by targeting NFKBIB. Tumour Biol., 2016, 37(1), 1261-1269.
[http://dx.doi.org/10.1007/s13277-015-3921-1] [PMID: 26286834]
[24]
Zheng, P.; Chen, L.; Yuan, X.; Luo, Q.; Liu, Y.; Xie, G.; Ma, Y.; Shen, L. Exosomal transfer of tumor-associated macrophage-derived miR-21 confers cisplatin resistance in gastric cancer cells. J. Exp. Clin. Cancer Res., 2017, 36(1), 53.
[http://dx.doi.org/10.1186/s13046-017-0528-y] [PMID: 28407783]
[25]
Gadalla, K.K.E.; Bailey, M.E.S.; Cobb, S.R. MeCP2 and Rett syndrome: Reversibility and potential avenues for therapy. Biochem. J., 2011, 439(1), 1-14.
[http://dx.doi.org/10.1042/BJ20110648] [PMID: 21916843]
[26]
Neupane, M.; Clark, A.P.; Landini, S.; Birkbak, N.J.; Eklund, A.C.; Lim, E.; Culhane, A.C.; Barry, W.T.; Schumacher, S.E.; Beroukhim, R.; Szallasi, Z.; Vidal, M.; Hill, D.E.; Silver, D.P. MECP2 is a frequently amplified oncogene with a novel epigenetic mechanism that mimics the role of activated RAS in malignancy. Cancer Discov., 2016, 6(1), 45-58.
[http://dx.doi.org/10.1158/2159-8290.CD-15-0341] [PMID: 26546296]
[27]
Müller, H.M.; Fiegl, H.; Goebel, G.; Hubalek, M.M.; Widschwendter, A.; Müller-Holzner, E.; Marth, C.; Widschwendter, M. MeCP2 and MBD2 expression in human neoplastic and non-neoplastic breast tissue and its association with oestrogen receptor status. Br. J. Cancer, 2003, 89(10), 1934-1939.
[http://dx.doi.org/10.1038/sj.bjc.6601392] [PMID: 14612906]
[28]
Franke, T.F.; Kaplan, D.R.; Cantley, L.C. PI3K: Downstream AKTion blocks apoptosis. Cell, 1997, 88(4), 435-437.
[http://dx.doi.org/10.1016/S0092-8674(00)81883-8] [PMID: 9038334]
[29]
Fresno Vara, J.A.; Casado, E.; de Castro, J.; Cejas, P.; Belda-Iniesta, C.; González-Barón, M. PI3K/Akt signalling pathway and cancer. Cancer Treat. Rev., 2004, 30(2), 193-204.
[http://dx.doi.org/10.1016/j.ctrv.2003.07.007] [PMID: 15023437]
[30]
Mora, A.; Komander, D.; van Aalten, D.M.; Alessi, D.R. PDK1, the master regulator of AGC kinase signal transduction. Semin. Cell Dev. Biol., 2004, 15(2), 161-170.
[http://dx.doi.org/10.1016/j.semcdb.2003.12.022] [PMID: 15209375]
[31]
Emmanouilidi, A.; Falasca, M. Targeting PDK1 for chemosensitization of cancer cells. Cancers (Basel), 2017, 9(10), 140.
[http://dx.doi.org/10.3390/cancers9100140] [PMID: 29064423]
[32]
Di Blasio, L.; Gagliardi, P.A.; Puliafito, A.; Primo, L. Serine/threonine kinase 3-phosphoinositide-dependent protein kinase-1 (PDK1) as a key regulator of cell migration and cancer dissemination. Cancers (Basel), 2017, 9(3), 25.
[http://dx.doi.org/10.3390/cancers9030025] [PMID: 28287465]
[33]
Falasca, M.; Chiozzotto, D.; Godage, H.Y.; Mazzoletti, M.; Riley, A.M.; Previdi, S.; Potter, B.V.; Broggini, M.; Maffucci, T. A novel inhibitor of the PI3K/Akt pathway based on the structure of inositol 1,3,4,5,6-pentakisphosphate. Br. J. Cancer, 2010, 102(1), 104-114.
[http://dx.doi.org/10.1038/sj.bjc.6605408] [PMID: 20051961]

Rights & Permissions Print Cite
Article Metrics
19
1
© 2024 Bentham Science Publishers | Privacy Policy