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Recent Patents on Anti-Cancer Drug Discovery

Author(s): Sadegh Paydari Rostami, Negar Moghare Dehkordi, Yazdan Asgari, Mohammad Reza Bolouri, Nasrin Shayanfar, Reza Falak and Gholam Ali Kardar*

DOI: 10.2174/1574892818666230330105016

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Competitive Effect of Overexpressed C-terminal of Snail-1 (CSnail) in Control of the Growth and Metastasis of Melanoma Cells

Page: [342 - 353] Pages: 12

  • * (Excluding Mailing and Handling)

Abstract

Background: Epithelial-to-mesenchymal transition (EMT) plays a role in the invasion and metastasis of cancer cells. During this phenomenon, Snail can promote tumor progression by upregulating mesenchymal factors and downregulating the expression of pro-apoptotic proteins.

Objective: Therefore, interventions on the expression rate of Snails may show beneficial therapeutic applications.

Methods: In this study, the C-terminal region of Snail1, capable of binding to E-box genomic sequences, was subcloned into the pAAV-IRES-EGFP backbone to make complete AAV-CSnail viral particles. B16F10 as a metastatic melanoma cell line, with a null expression of wild type TP53 was transduced by AAV-CSnail. Moreover, the transduced cells were analyzed for in vitro expression of apoptosis, migration, and EMT-related genes, and in vivo inhibition of metastasis.

Results: In more than 80% of the AAV-CSnail transduced cells, the CSnail gene expression competitively reduced the wild-type Snail functionality and consequently lowered the mRNA expression level of EMT-related genes. Furthermore, the transcription level of cell cycle inhibitory factor p21 and pro-apoptotic factors were promoted. The scratch test showed a decrease in the migration ability of AAV-CSnail transduced group compared to control. Finally, metastasis of cancer cells to lung tissue in the AAV-CSnail-treated B16F10 melanoma mouse model was significantly reduced, pointing out to prevention of EMT by the competitive inhibitory effect of CSnail on Snail1 and increased apoptosis of B16F10 cells.

Conclusion: The capability of this successful competition in reducing the growth, invasion, and metastasis of melanoma cells indicates that gene therapy is a promising strategy for the control of the growth and metastasis of cancer cells.

[1]
Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol 2014; 15(3): 178-96.
[http://dx.doi.org/10.1038/nrm3758] [PMID: 24556840]
[2]
Weinberg RA. The biology of cancer. (2nd ed.), W.W. Norton & Company: New York, 2013.
[http://dx.doi.org/10.1201/9780429258794]
[3]
Shibue T, Weinberg RA. EMT, CSCs, and drug resistance: The mechanistic link and clinical implications. Nat Rev Clin Oncol 2017; 14(10): 611-29.
[http://dx.doi.org/10.1038/nrclinonc.2017.44] [PMID: 28397828]
[4]
Brabletz T, Kalluri R, Nieto MA, Weinberg RA. EMT in cancer. Nat Rev Cancer 2018; 18(2): 128-34.
[http://dx.doi.org/10.1038/nrc.2017.118] [PMID: 29326430]
[5]
Micalizzi DS, Farabaugh SM, Ford HL. Epithelial-mesenchymal transition in cancer: Parallels between normal development and tumor progression. J Mammary Gland Biol Neoplasia 2010; 15(2): 117-34.
[http://dx.doi.org/10.1007/s10911-010-9178-9] [PMID: 20490631]
[6]
Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest 2009; 119(6): 1420-8.
[http://dx.doi.org/10.1172/JCI39104] [PMID: 19487818]
[7]
Winton D, Junaid F, Tomic G, Kemp R. Single-copy Snail upregulation causes partial epithelial-mesenchymal transition in colon cancer cells. BMC Cancer 2023; 23(1): 153.
[http://dx.doi.org/10.17863/CAM.93495]
[8]
Tran HD, Luitel K, Kim M, Zhang K, Longmore GD, Tran DD. Transient SNAIL1 expression is necessary for metastatic competence in breast cancer. Cancer Res 2014; 74(21): 6330-40.
[http://dx.doi.org/10.1158/0008-5472.CAN-14-0923] [PMID: 25164016]
[9]
Zheng X, Carstens JL, Kim J, et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 2015; 527(7579): 525-30.
[http://dx.doi.org/10.1038/nature16064] [PMID: 26560028]
[10]
Georgess D, Padmanaban V, Sirka OK, et al. Twist1-induced epithelial dissemination requires Prkd1 signaling. Cancer Res 2020; 80(2): 204-18.
[http://dx.doi.org/10.1158/0008-5472.CAN-18-3241] [PMID: 31676574]
[11]
Gholami MD, Falak R, Heidari S, et al. A truncated snail1 transcription factor alters the expression of essential EMT markers and suppresses tumor cell migration in a human lung cancer cell line. Rec Pat Anticancer Drug Discov 2019; 14(2): 158-69.
[http://dx.doi.org/10.2174/1574892814666190527111429] [PMID: 31131753]
[12]
Krebs AM, Mitschke J, Lasierra Losada M, et al. The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat Cell Biol 2017; 19(5): 518-29.
[http://dx.doi.org/10.1038/ncb3513] [PMID: 28414315]
[13]
Wu K, Bonavida B. The activated NF-κB-snail-RKIP circuitry in cancer regulates both the metastatic cascade and resistance to apoptosis by cytotoxic drugs. Crit Rev Immunol 2009; 29(3): 241-54.
[14]
Vega S, Morales AV, Ocaña OH, Valdés F, Fabregat I, Nieto MA. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev 2004; 18(10): 1131-43.
[http://dx.doi.org/10.1101/gad.294104] [PMID: 15155580]
[15]
Puisieux A, Brabletz T, Caramel J. Oncogenic roles of EMT-inducing transcription factors. Nat Cell Biol 2014; 16(6): 488-94.
[http://dx.doi.org/10.1038/ncb2976] [PMID: 24875735]
[16]
Gonzalez DM, Medici D. Signaling mechanisms of the epithelial-mesenchymal transition. Sci Signal 2014; 7(344): re8.
[http://dx.doi.org/10.1126/scisignal.2005189] [PMID: 25249658]
[17]
Barrallo-Gimeno A, Nieto MA. The Snail genes as inducers of cell movement and survival: Implications in development and cancer. Development 2005; 132(14): 3151-61.
[http://dx.doi.org/10.1242/dev.01907] [PMID: 15983400]
[18]
Stasiak M, Boncela J, Perreau C, et al. Lumican inhibits SNAIL-induced melanoma cell migration specifically by blocking MMP-14 activity. PLoS One 2016; 11(3): e0150226.
[http://dx.doi.org/10.1371/journal.pone.0150226] [PMID: 26930497]
[19]
Veloso ES, Gonçalves INN, Silveira TL, et al. ZEB and Snail expression indicates epithelial-mesenchymal transition in canine melanoma. Res Vet Sci 2020; 131: 7-14.
[http://dx.doi.org/10.1016/j.rvsc.2020.04.007] [PMID: 32278962]
[20]
Wels C, Joshi S, Koefinger P, Bergler H, Schaider H. Transcriptional activation of ZEB1 by Slug leads to cooperative regulation of the epithelial-mesenchymal transition-like phenotype in melanoma. J Invest Dermatol 2011; 131(9): 1877-85.
[http://dx.doi.org/10.1038/jid.2011.142] [PMID: 21593765]
[21]
Wang J, He H, Jiang Q III, Wang Y, Jia S. CBX6 promotes HCC metastasis via transcription factors snail/zeb1-mediated EMT mechanism. OncoTargets Ther 2020; 13: 12489-500.
[http://dx.doi.org/10.2147/OTT.S257363] [PMID: 33311989]
[22]
Nieto MA. The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol 2002; 3(3): 155-66.
[http://dx.doi.org/10.1038/nrm757] [PMID: 11994736]
[23]
Kaufhold S, Bonavida B. Central role of Snail1 in the regulation of EMT and resistance in cancer: A target for therapeutic intervention. J Exp Clin Cancer Res 2014; 33(1): 62.
[http://dx.doi.org/10.1186/s13046-014-0062-0] [PMID: 25084828]
[24]
Wu HT, Zhong HT, Li GW, et al. Oncogenic functions of the EMT-related transcription factor ZEB1 in breast cancer. J Transl Med 2020; 18(1): 51.
[http://dx.doi.org/10.1186/s12967-020-02240-z] [PMID: 32014049]
[25]
AAV-2 helper free packaging system. CELL BIOLABS, INC. Available From: https://www.cellbiolabs.com/aav-2-packaging-system
[26]
Chandler LC, Barnard AR, Caddy SL, et al. Enhancement of adeno-associated virus-mediated gene therapy using hydroxychloroquine in murine and human tissues. Mol Ther Methods Clin Dev 2019; 14: 77-89.
[http://dx.doi.org/10.1016/j.omtm.2019.05.012] [PMID: 31309129]
[27]
Rodriguez LG, Wu X, Guan J-L. Wound-healing assay. In: Cell migration. Springer: US, 2005; pp. 23-9.
[28]
Fidler IJ. Selection of successive tumour lines for metastasis. Nat New Biol 1973; 242(118): 148-9.
[http://dx.doi.org/10.1038/newbio242148a0] [PMID: 4512654]
[29]
Fidler IJ. Biological behavior of malignant melanoma cells correlated to their survival in vivo. Cancer Res 1975; 35(1): 218-24.
[PMID: 1109790]
[30]
Mathieu V, Le Mercier M, De Neve N, et al. Galectin-1 knockdown increases sensitivity to temozolomide in a B16F10 mouse metastatic melanoma model. J Invest Dermatol 2007; 127(10): 2399-410.
[http://dx.doi.org/10.1038/sj.jid.5700869] [PMID: 17495956]
[31]
Fares J, Fares MY, Khachfe HH, Salhab HA, Fares Y. Molecular principles of metastasis: A hallmark of cancer revisited. Signal Transduct Target Ther 2020; 5(1): 28.
[http://dx.doi.org/10.1038/s41392-020-0134-x] [PMID: 32296047]
[32]
Georgakopoulos-Soares I, Chartoumpekis DV, Kyriazopoulou V, Zaravinos A. EMT factors and metabolic pathways in cancer. Front Oncol 2020; 10: 499.
[http://dx.doi.org/10.3389/fonc.2020.00499] [PMID: 32318352]
[33]
Inoue A, Seidel MG, Wu W, et al. Slug, a highly conserved zinc finger transcriptional repressor, protects hematopoietic progenitor cells from radiation-induced apoptosis in vivo. Cancer Cell 2002; 2(4): 279-88.
[http://dx.doi.org/10.1016/S1535-6108(02)00155-1] [PMID: 12398892]
[34]
Metzstein MM, Horvitz HR. The C. elegans cell death specification gene ces-1 encodes a snail family zinc finger protein. Mol Cell 1999; 4(3): 309-19.
[http://dx.doi.org/10.1016/S1097-2765(00)80333-0] [PMID: 10518212]
[35]
Pérez-Losada J, Sánchez-Martín M, Pérez-Caro M, Pérez-Mancera PA, Sánchez-García I. The radioresistance biological function of the SCF/kit signaling pathway is mediated by the zinc-finger transcription factor Slug. Oncogene 2003; 22(27): 4205-11.
[http://dx.doi.org/10.1038/sj.onc.1206467] [PMID: 12833143]
[36]
Semenov O, Daks A, Fedorova O, Shuvalov O, Barlev NA. Opposing roles of wild-type and mutant p53 in the process of epithelial to mesenchymal transition. Front Mol Biosci 2022; 9: 928399.
[http://dx.doi.org/10.3389/fmolb.2022.928399] [PMID: 35813818]
[37]
Kajita M, McClinic KN, Wade PA. Aberrant expression of the transcription factors snail and slug alters the response to genotoxic stress. Mol Cell Biol 2004; 24(17): 7559-66.
[http://dx.doi.org/10.1128/MCB.24.17.7559-7566.2004] [PMID: 15314165]
[38]
Kurrey NK, Jalgaonkar SP, Joglekar AV, et al. Snail and slug mediate radioresistance and chemoresistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. Stem Cells 2009; 27(9): 2059-68.
[http://dx.doi.org/10.1002/stem.154] [PMID: 19544473]
[39]
Yang X, Han M, Han H, et al. Silencing Snail suppresses tumor cell proliferation and invasion by reversing epithelial-to-mesenchymal transition and arresting G2/M phase in non-small cell lung cancer. Int J Oncol 2017; 50(4): 1251-60.
[http://dx.doi.org/10.3892/ijo.2017.3888] [PMID: 28259904]
[40]
Takahashi E, Funato N, Higashihori N, Hata Y, Gridley T, Nakamura M. Snail regulates p21WAF/CIP1 expression in cooperation with E2A and Twist. Biochem Biophys Res Commun 2004; 325(4): 1136-44.
[http://dx.doi.org/10.1016/j.bbrc.2004.10.148] [PMID: 15555546]
[41]
Ni T, Li XY, Lu N, et al. Snail1-dependent p53 repression regulates expansion and activity of tumour-initiating cells in breast cancer. Nat Cell Biol 2016; 18(11): 1221-32.
[http://dx.doi.org/10.1038/ncb3425] [PMID: 27749822]
[42]
Li HM, Bi YR, Li Y, et al. A potent CBP/p300-Snail interaction inhibitor suppresses tumor growth and metastasis in wild-type p53-expressing cancer. Sci Adv 2020; 6(17): eaaw8500.
[http://dx.doi.org/10.1126/sciadv.aaw8500] [PMID: 32494626]
[43]
Li Y, Ren B, Li H, Lu T, Fu R, Wu Z. Omeprazole suppresses aggressive cancer growth and metastasis in mice through promoting Snail degradation. Acta Pharmacol Sin 2022; 43(7): 1816-28.
[http://dx.doi.org/10.1038/s41401-021-00787-1] [PMID: 34785782]
[44]
Lu L, Chen Z, Lin X, et al. Inhibition of BRD4 suppresses the malignancy of breast cancer cells via regulation of Snail. Cell Death Differ 2020; 27(1): 255-68.
[http://dx.doi.org/10.1038/s41418-019-0353-2] [PMID: 31114028]