Effect of ReNeg-AID peptide overexpression in MDA-MB-231 triple-negative breast cancer cells: the noncanonical Notch pathway
Main Article Content
Germán Saucedo-Correa
http://orcid.org/0000-0003-1468-1268
Rosa E. Nuñez-Anita
http://orcid.org/0000-0002-1117-9136
Ulises Maciel-Ponce
http://orcid.org/0009-0003-1524-9474
Humberto Contreras-Cornejo
http://orcid.org/0009-0000-1713-6244
Alejandro Bravo-Patiño
http://orcid.org/0000-0001-9897-7634
http://orcid.org/0000-0003-1468-1268
Rosa E. Nuñez-Anita
http://orcid.org/0000-0002-1117-9136
Ulises Maciel-Ponce
http://orcid.org/0009-0003-1524-9474
Humberto Contreras-Cornejo
http://orcid.org/0009-0000-1713-6244
Alejandro Bravo-Patiño
http://orcid.org/0000-0001-9897-7634
Abstract
The Notch pathway has two general regulatory mechanisms: its canonical pathway and the non-canonical pathway. The non-canonical Notch pathway is known that acts independently of its transcriptional factor to activate its target genes which do not belong to the HER, HES and HERP gene family, and has been linked to oncogenic processes and immune cell activation. Here we report the behavior of triple-negative breast cancer cells that maintain high activity of the non-canonical Notch pathway at the presence of ReNeg-AID a peptide which seems to be provoking both a change in the phenotype of the triple-negative breast cancer cells from epithelial cell to non-functional mesenchymal cell, as well as a cell's attempt to regain canonical Notch pathway activity. Finally, overexpression of the ReNeg-AID peptide in the triple-negative breast cancer cell line promoted a negative regulation of its transcriptional factor, intensifying the non-canonical Notch pathway activity and causing an oscillation or combination between the activities of the canonical and non-canonical mechanisms of Notch pathway due to the activation of Notch-1 and 3 receptors and the repression of Notch-2 and 4. Added to this must be the interactions that exist between Notch pathway with other signaling pathways that may also be in a state of deregulation in the cancer microenvironment.
Keywords:
ReNeg-AID peptide, Non-canonical Notch pathway, Triple-negative breast cancer, MDA-MB-231 cells, Notch receptors, Canonical Notch pathway, Phenotypic change, Oncogenic processes, Signal pathway interaction, Cancer microenvironment
Article Details
How to Cite
SAUCEDO-CORREA, Germán et al.
Effect of ReNeg-AID peptide overexpression in MDA-MB-231 triple-negative breast cancer cells: the noncanonical Notch pathway.
Medical Research Archives, [S.l.], v. 12, n. 10, oct. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5814>. Date accessed: 15 nov. 2024.
doi: https://doi.org/10.18103/mra.v12i10.5814.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
[1]. Sade H, Krishna S, Sarin A. The Anti-apoptotic Effect of Notch-1 Requires p56lck-dependent, Akt/PKB-mediated Signaling in T Cells. J. Biol. Chem. 2004;279:2937–2944. https://doi.org/10.1074/jbc.m309924200.
[2]. Allenspach EJ, Maillard I. Notch Signaling in Cancer. Cancer Biol. Ther. 2002;1:466–476. https://doi.org/10.4161/cbt.1.5.159.
[3]. Behrens J, Lustig B. The Wnt connection to tumorigenesis. Int. J. Dev. Biol. 2004;48:477–487. https://doi.org/10.1387/ijdb.041815jb.
[4]. Di Mauro C, Rosa R, D'Amato V, Ciciola P, Servetto A, Marciano R, Orsini RC, Formisano L, De Falco S, Cicatiello V, Di Bonito M, Cantile M, Collina F, Chambery A, Veneziani BM, De Placido S, Bianco R. Hedgehog signalling pathway orchestrates angiogenesis in triple-negative breast cancers. Br. J. Cancer. 2017;116:1425–1435. https://doi.org/10.1038/bjc.2017.116.
[5]. Dongre A, Surampudi L, Lawlor RG, Fauq AH, Miele L, Golde TE, Minter LM, Osborne BA. Non-canonical Notch signaling drives activation and differentiation of peripheral CD4+ T cells. Front. Immunol. 2014;5:1–14. https://doi.org/10.3389/fimmu.2014.00054
[6]. Maier D. The evolution of transcriptional repressors in the Notch signaling pathway: a computational analysis. Hereditas. 2019;156:5. https://doi.org/10.1186/s41065-019-0081-0
[7]. Zeng C, Xing R, Liu J, Xing F. Role of CSL-dependent and independent Notch signaling pathways in cell apoptosis. Apoptosis. 2016;21:1–12. https://doi.org/10.1007/s10495-015-1188-z
[8]. Ayaz F, Osborne BA. Non-canonical Notch signaling in cancer and immunity, Front. Oncol. 2014;4:1–7. https://doi.org/10.3389/fonc.2014.00345
[9]. Brechbiel J, Miller-Moslin K, Adjei AA. Crosstalk between hedgehog and other signaling pathways as a basis for combination therapies in cancer. Cancer. Treat. Rev. 2014;40:750–759. https://doi.org/10.1016/j.ctrv.2014.02.003.
[10]. Salmena L, Carracedo A, Pandolfi PP. Tenets of PTEN Tumor Suppression. Cell. 2008;133:403–414. https://doi.org/10.1016/j.cell.2008.04.013.
[11]. Hossain F, Sorrentino C, Ucar DA, Peng Y, Matossian M, Wyczechowska D, Crabtree J, Zabaleta J, Morello S, Del Valle L, Burow M, Collins-Burow B, Pannuti A, Minter LM, Golde TE, Osborne BA, Miele L. Notch Signaling Regulates Mitochondrial Metabolism and NF-kB Activity in Triple-Negative Breast Cancer Cells via IKKa-Dependent Non-canonical Pathways. Front. Oncol. 2018;8:575. https://doi.org/10.3389/fonc.2018.00575.
[12]. Minter LM, Osborne BA. Canonical and non-canonical Notch signaling in CD4+ T cells. Curr. Top. Microbiol. Immunol. 2012;360:99–114. https://doi.org/10.1007/82_2012_233.
[13]. Kyu-Sun Lee L, Wu Z, Song Y, Mitra SS, Feroze AH, Cheshier SH, Lu B. Roles of PINK1, mTORC2, and mitochondria in preserving brain tumor-forming stem cells in a noncanonical Notch signaling pathway. Genes Dev. 2013;27:2642–2647. https://doi.org/10.1101/gad.225169.113.
[14]. Thorsen J, Micci F, Heim S. Identification of chromosomal breakpoints of cancer-specific translocations by rolling circle amplification and long-distance inverse PCR. Cancer Genet. 2011; 204:458–461. https://doi.org/10.1016/j.cancergen.2011.07.007.
[15]. Saucedo-Correa G, Nuñez-Anita RE, Maciel-Ponce U, Contreras-Cornejo H, Bravo-Patiño A. A peptide derived from D. melanogaster Hairless protein promotes the negative regulation of Notch aberrant constitutive signaling on human breast cancer cells. Int. J. Clin. Exp. Med. 2021;14:62-75. https://e-century.us/files/ijcem/14/1/ijcem0108892.pdf.
[16]. Contreras-Cornejo H, Saucedo-Correa G, Oviedo-Boyso J, Valdez-Alarcón JJ, Baizabal-Aguirre VM, Cajero-Juárez M, Bravo-Patiño A. The CSL proteins, versatile transcription factors and context dependent corepressors of the notch signaling pathway. Cell. Div. 2016;11:12. https://doi.org/10.1186/s13008-016-0025-2.
[17]. Pedrosa AR, Trindade A, Carvalho C, Graça J, Carvalho S, Peleteiro MC, Adams RH, Duarte A. Endothelial Jagged1 promotes solid tumor growth through both pro-angiogenic and angiocrine functions. Oncotarget. 2015;6:24404-24423. https://doi.org/10.18632/oncotarget.4380.
[18]. Weijzen S, Rizzo P, Braid M, Vaishnav R, Jonkheer SM, Zlobin A, Osborne BA, Gottipati S, Aster JC, Hahn WC, Rudolf M, Siziopikou K, Kast WM, Miele L. Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nat. Med. 2002;8:979–986. https://doi.org/10.1038/nm754.
[19]. Asnaghi L, Lin MH, Lim KS, Lim KJ, Tripathy A, Wendeborn M, Merbs SL, Handa JT, Sodhi A, Bar EE, Eberhart CG. Hypoxia promotes uveal melanoma invasion through enhanced notch and MAPK activation. PLoS One. 2014;9:e105372. https://doi.org/10.1371/journal.pone.0105372.
[20]. Hartman J, Müller P, Foster JS, Wimalasena J, Gustafsson JA, Ström A. HES-1 inhibits 17beta-estradiol and heregulin-beta1-mediated upregulation of E2F-1. Oncogene. 2004;23:8826–8833. https://doi.org/10.1038/sj.onc.1208139.
[21]. Corbin EA, Kong F, Lim CT, King WP, Bashir R. Biophysical properties of human breast cancer cells measured using silicon MEMS resonators and atomic force microscopy. Lab. Chip. 2015;15:839–847. https://doi.org/10.1039/c4lc01179a.
[22]. Karamboulas C, Ailles L. Developmental signaling pathways in cancer stem cells of solid tumors. Biochim. Biophys. Acta. 2013;1830:2481–2495. https://doi.org/10.1016/j.bbagen.2012.11.008.
[23]. Zhang J, Tian XJ, Xing J. Signal Transduction Pathways of EMT Induced by TGF-β, SHH, and WNT and Their Crosstalks. J. Clin. Med. 2016;5:41. https://doi.org/10.3390/jcm5040041.
[24]. Guo S, Liu M, Gonzalez-Perez RR. Role of Notch and its oncogenic signaling crosstalk in breast cancer. Biochim. Biophys. Acta. 2011;1815:197-213. https://doi.org/10.1016/j.bbcan.2010.12.002.
[25]. Sanchez-Vega F, Mina M, Armenia J, Chatila WK, Luna A, La KC, Dimitriadoy S, Liu DL, Kantheti HS, Saghafinia S, Chakravarty D, Daian F, Gao Q, Bailey MH, Liang WW, Foltz SM, Shmulevich I, Ding L, Heins Z, Ochoa A, Gross B, Gao J, Zhang H, Kundra R, Kandoth C, Bahceci I, Dervishi L, Dogrusoz U, Zhou W, Shen H, Laird PW, Way GP, Greene CS, Liang H, Xiao Y, Wang C, Lavarone A, Berger AH, Bivona TG, Lazar AJ, Hammer GD, Giordano T, Kwong LN, McArthur G, Huang C, Tward AD, Frederick MJ, McCormick F, Meyerson M, Van Allen EM, Cherniack AD, Ciriello G, Sander C, Schultz N. Oncogenic Signaling Pathways in The Cancer Genome Atlas. Cell. 2018;173:321-337. https://doi.org/10.1016/j.cell.2018.03.035.
[26]. Perumalsamy LR, Nagala M, Banerjee P, Sarin A. A hierarchical cascade activated by non-canonical Notch signaling and the mTOR-Rictor complex regulates neglect-induced death in mammalian cells. Cell Death & Differentiation. 2009;16:879–889. https://www.nature.com/articles/cdd200920.
[27]. Wang Z, Zhang Y, Li Y, Banerjee S, Liao J, Sarkar FH. Down-regulation of Notch-1 contributes to cell growth inhibition and apoptosis in pancreatic cancer cells. Mol. Cancer Ther. 2006;5:483–493. https://doi.org/10.1158/1535-7163.mct-05-0299.
[28]. Arnold A, Papanikolaou A. Cyclin D1 in breast cancer pathogenesis. J. Clin. Oncol. 2005;23:4215 –4224. https://doi.org/10.1200/jco.2005.05.064.
[29]. Sweeney KJ, Swarbrick A, Sutherland RL, Musgrove EA. Lack of relationship between CDK activity and G1 cyclin expression in breast cancer cells. Oncogene. 1998;16:2865–2878. https://doi.org/10.1038/sj.onc.1201814.
[2]. Allenspach EJ, Maillard I. Notch Signaling in Cancer. Cancer Biol. Ther. 2002;1:466–476. https://doi.org/10.4161/cbt.1.5.159.
[3]. Behrens J, Lustig B. The Wnt connection to tumorigenesis. Int. J. Dev. Biol. 2004;48:477–487. https://doi.org/10.1387/ijdb.041815jb.
[4]. Di Mauro C, Rosa R, D'Amato V, Ciciola P, Servetto A, Marciano R, Orsini RC, Formisano L, De Falco S, Cicatiello V, Di Bonito M, Cantile M, Collina F, Chambery A, Veneziani BM, De Placido S, Bianco R. Hedgehog signalling pathway orchestrates angiogenesis in triple-negative breast cancers. Br. J. Cancer. 2017;116:1425–1435. https://doi.org/10.1038/bjc.2017.116.
[5]. Dongre A, Surampudi L, Lawlor RG, Fauq AH, Miele L, Golde TE, Minter LM, Osborne BA. Non-canonical Notch signaling drives activation and differentiation of peripheral CD4+ T cells. Front. Immunol. 2014;5:1–14. https://doi.org/10.3389/fimmu.2014.00054
[6]. Maier D. The evolution of transcriptional repressors in the Notch signaling pathway: a computational analysis. Hereditas. 2019;156:5. https://doi.org/10.1186/s41065-019-0081-0
[7]. Zeng C, Xing R, Liu J, Xing F. Role of CSL-dependent and independent Notch signaling pathways in cell apoptosis. Apoptosis. 2016;21:1–12. https://doi.org/10.1007/s10495-015-1188-z
[8]. Ayaz F, Osborne BA. Non-canonical Notch signaling in cancer and immunity, Front. Oncol. 2014;4:1–7. https://doi.org/10.3389/fonc.2014.00345
[9]. Brechbiel J, Miller-Moslin K, Adjei AA. Crosstalk between hedgehog and other signaling pathways as a basis for combination therapies in cancer. Cancer. Treat. Rev. 2014;40:750–759. https://doi.org/10.1016/j.ctrv.2014.02.003.
[10]. Salmena L, Carracedo A, Pandolfi PP. Tenets of PTEN Tumor Suppression. Cell. 2008;133:403–414. https://doi.org/10.1016/j.cell.2008.04.013.
[11]. Hossain F, Sorrentino C, Ucar DA, Peng Y, Matossian M, Wyczechowska D, Crabtree J, Zabaleta J, Morello S, Del Valle L, Burow M, Collins-Burow B, Pannuti A, Minter LM, Golde TE, Osborne BA, Miele L. Notch Signaling Regulates Mitochondrial Metabolism and NF-kB Activity in Triple-Negative Breast Cancer Cells via IKKa-Dependent Non-canonical Pathways. Front. Oncol. 2018;8:575. https://doi.org/10.3389/fonc.2018.00575.
[12]. Minter LM, Osborne BA. Canonical and non-canonical Notch signaling in CD4+ T cells. Curr. Top. Microbiol. Immunol. 2012;360:99–114. https://doi.org/10.1007/82_2012_233.
[13]. Kyu-Sun Lee L, Wu Z, Song Y, Mitra SS, Feroze AH, Cheshier SH, Lu B. Roles of PINK1, mTORC2, and mitochondria in preserving brain tumor-forming stem cells in a noncanonical Notch signaling pathway. Genes Dev. 2013;27:2642–2647. https://doi.org/10.1101/gad.225169.113.
[14]. Thorsen J, Micci F, Heim S. Identification of chromosomal breakpoints of cancer-specific translocations by rolling circle amplification and long-distance inverse PCR. Cancer Genet. 2011; 204:458–461. https://doi.org/10.1016/j.cancergen.2011.07.007.
[15]. Saucedo-Correa G, Nuñez-Anita RE, Maciel-Ponce U, Contreras-Cornejo H, Bravo-Patiño A. A peptide derived from D. melanogaster Hairless protein promotes the negative regulation of Notch aberrant constitutive signaling on human breast cancer cells. Int. J. Clin. Exp. Med. 2021;14:62-75. https://e-century.us/files/ijcem/14/1/ijcem0108892.pdf.
[16]. Contreras-Cornejo H, Saucedo-Correa G, Oviedo-Boyso J, Valdez-Alarcón JJ, Baizabal-Aguirre VM, Cajero-Juárez M, Bravo-Patiño A. The CSL proteins, versatile transcription factors and context dependent corepressors of the notch signaling pathway. Cell. Div. 2016;11:12. https://doi.org/10.1186/s13008-016-0025-2.
[17]. Pedrosa AR, Trindade A, Carvalho C, Graça J, Carvalho S, Peleteiro MC, Adams RH, Duarte A. Endothelial Jagged1 promotes solid tumor growth through both pro-angiogenic and angiocrine functions. Oncotarget. 2015;6:24404-24423. https://doi.org/10.18632/oncotarget.4380.
[18]. Weijzen S, Rizzo P, Braid M, Vaishnav R, Jonkheer SM, Zlobin A, Osborne BA, Gottipati S, Aster JC, Hahn WC, Rudolf M, Siziopikou K, Kast WM, Miele L. Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nat. Med. 2002;8:979–986. https://doi.org/10.1038/nm754.
[19]. Asnaghi L, Lin MH, Lim KS, Lim KJ, Tripathy A, Wendeborn M, Merbs SL, Handa JT, Sodhi A, Bar EE, Eberhart CG. Hypoxia promotes uveal melanoma invasion through enhanced notch and MAPK activation. PLoS One. 2014;9:e105372. https://doi.org/10.1371/journal.pone.0105372.
[20]. Hartman J, Müller P, Foster JS, Wimalasena J, Gustafsson JA, Ström A. HES-1 inhibits 17beta-estradiol and heregulin-beta1-mediated upregulation of E2F-1. Oncogene. 2004;23:8826–8833. https://doi.org/10.1038/sj.onc.1208139.
[21]. Corbin EA, Kong F, Lim CT, King WP, Bashir R. Biophysical properties of human breast cancer cells measured using silicon MEMS resonators and atomic force microscopy. Lab. Chip. 2015;15:839–847. https://doi.org/10.1039/c4lc01179a.
[22]. Karamboulas C, Ailles L. Developmental signaling pathways in cancer stem cells of solid tumors. Biochim. Biophys. Acta. 2013;1830:2481–2495. https://doi.org/10.1016/j.bbagen.2012.11.008.
[23]. Zhang J, Tian XJ, Xing J. Signal Transduction Pathways of EMT Induced by TGF-β, SHH, and WNT and Their Crosstalks. J. Clin. Med. 2016;5:41. https://doi.org/10.3390/jcm5040041.
[24]. Guo S, Liu M, Gonzalez-Perez RR. Role of Notch and its oncogenic signaling crosstalk in breast cancer. Biochim. Biophys. Acta. 2011;1815:197-213. https://doi.org/10.1016/j.bbcan.2010.12.002.
[25]. Sanchez-Vega F, Mina M, Armenia J, Chatila WK, Luna A, La KC, Dimitriadoy S, Liu DL, Kantheti HS, Saghafinia S, Chakravarty D, Daian F, Gao Q, Bailey MH, Liang WW, Foltz SM, Shmulevich I, Ding L, Heins Z, Ochoa A, Gross B, Gao J, Zhang H, Kundra R, Kandoth C, Bahceci I, Dervishi L, Dogrusoz U, Zhou W, Shen H, Laird PW, Way GP, Greene CS, Liang H, Xiao Y, Wang C, Lavarone A, Berger AH, Bivona TG, Lazar AJ, Hammer GD, Giordano T, Kwong LN, McArthur G, Huang C, Tward AD, Frederick MJ, McCormick F, Meyerson M, Van Allen EM, Cherniack AD, Ciriello G, Sander C, Schultz N. Oncogenic Signaling Pathways in The Cancer Genome Atlas. Cell. 2018;173:321-337. https://doi.org/10.1016/j.cell.2018.03.035.
[26]. Perumalsamy LR, Nagala M, Banerjee P, Sarin A. A hierarchical cascade activated by non-canonical Notch signaling and the mTOR-Rictor complex regulates neglect-induced death in mammalian cells. Cell Death & Differentiation. 2009;16:879–889. https://www.nature.com/articles/cdd200920.
[27]. Wang Z, Zhang Y, Li Y, Banerjee S, Liao J, Sarkar FH. Down-regulation of Notch-1 contributes to cell growth inhibition and apoptosis in pancreatic cancer cells. Mol. Cancer Ther. 2006;5:483–493. https://doi.org/10.1158/1535-7163.mct-05-0299.
[28]. Arnold A, Papanikolaou A. Cyclin D1 in breast cancer pathogenesis. J. Clin. Oncol. 2005;23:4215 –4224. https://doi.org/10.1200/jco.2005.05.064.
[29]. Sweeney KJ, Swarbrick A, Sutherland RL, Musgrove EA. Lack of relationship between CDK activity and G1 cyclin expression in breast cancer cells. Oncogene. 1998;16:2865–2878. https://doi.org/10.1038/sj.onc.1201814.