Login Register Cart 0
Generic placeholder image

Current Cancer Drug Targets

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 Chinese
Research Article

EGF/EGFR Promotes Salivary Adenoid Cystic Carcinoma Cell Malignant Neural Invasion via Activation of PI3K/AKT and MEK/ERK Signaling

Author(s): Yixiong Ren, Yonglong Hong, Wenting He, Yakun Liu, Wenge Chen, Sui Wen* and Moyi Sun*

Volume 22, Issue 7, 2022

Published on: 09 June, 2022

Page: [603 - 616] Pages: 14

DOI: 10.2174/1568009622666220411112312

Price: $65

Abstract

Background: Salivary adenoid cystic carcinoma (SACC) is one of the most common malignant cancers of the salivary gland, and 32.4-72.0% of SACC cases exhibit neural invasion (NI); however, the molecular mechanism underlying the high invasion potential of SACC remains unclear.

Methods: The present study investigated the role of epidermal growth factor receptor (EGFR) in the AKT inhibition- or mitogen-activated protein kinase kinase (MEK)-induced NI and epithelialmesenchymal transition (EMT) in SACC cells using EGFR, PI3K, and MEK inhibitors. SACC-83 cell viability was assessed using an MTT assay, and a wound healing assay was performed to evaluate cell migration. Immunohistochemical staining with streptavidin peroxidase was used to detect the positive expression rate of EMT, AKT, phosphorylated (p)-AKT, ERK, and p-ERK proteins. The impact of EGFR, PI3K, and MEK inhibitors on tumor growth and NI was examined in a xenograft model in nude mice.

Results: EGF and EGFR are effective in increasing cell viability, migration, and invasion. SACC metastasis is affected by the PI3K/AKT and MEK/ERK pathways, both of which are initiated by EGF/EGFR. The EMT and NI are regulated by the EGF/EGFR, PI3K/AKT, and MEK/ERK pathways. The present findings demonstrate the importance of suppressed EGFR/AKT/MEK signaling in NI in SACC by neural-tumor co-culture in vitro. Furthermore, our preclinical experiment provides solid evidence that injection of EGFR, PI3K, and MEK inhibitors suppressed the tumor growth and NI of SACC cells in nude mice.

Conclusion: It was identified that inhibitors of EGFR, PI3K/AKT or MEK/ERK suppressed the proliferation, migration, and NI of SACC-83 cells via downregulation of the PI3K/AKT or MEK/ERK pathways. It was also demonstrated that inhibition of EGFR abolishes EMT in SACC by inhibiting the signaling of PI3K/AKT and MEK/ERK. The present results suggest the potential effectiveness of targeting multiple oncogenes associated with downstream pathways of EGF/EGFR, as well as potential therapeutic targets to limit NI in SACC by PI3K/AKT or MEK/ERK inhibition.

Keywords: EGF/EGFR pathway, PI3K/AKT pathway, MEK/ERK pathway, salivary adenoid cystic carcinoma, neural invasion, therapeutic target.

« Previous
Graphical Abstract

[1]
Weng, L.X.; Wang, G.H.; Yao, H.; Yu, M.F.; Lin, J. Epigallocatechin gallate inhibits the growth of salivary adenoid cystic carcinoma cells via the EGFR/Erk signal transduction pathway and the mitochondria apoptosis pathway. Neoplasma, 2017, 64(4), 563-570.
[http://dx.doi.org/10.4149/neo_2017_410] [PMID: 28485162]
[2]
Xu, B.; Drill, E.; Ho, A.; Ho, A.; Dunn, L.; Prieto-Granada, C.N.; Chan, T.; Ganly, I.; Ghossein, R.; Katabi, N. Predictors of outcome in adenoid cystic carcinoma of salivary glands: A clinicopathologic study with correlation between MYB fusion and protein expression. Am. J. Surg. Pathol., 2017, 41(10), 1422-1432.
[http://dx.doi.org/10.1097/PAS.0000000000000918] [PMID: 28719465]
[3]
Jang, S.; Patel, P.N.; Kimple, R.J.; McCulloch, T.M. Clinical outcomes and prognostic factors of adenoid cystic carcinoma of the head and neck. Anticancer Res., 2017, 37(6), 3045-3052.
[PMID: 28551643]
[4]
Dai, W.; Yao, Y.; Zhou, Q.; Sun, C.F. Ubiquitin-specific peptidase 22, a histone deubiquitinating enzyme, is a novel poor prognostic factor for salivary adenoid cystic carcinoma. PLoS One, 2014, 9(1)e87148
[http://dx.doi.org/10.1371/journal.pone.0087148] [PMID: 24466336]
[5]
Xu, P.; Wang, S.; Luo, Y.; Yin, J.; Belkacemi, Y.; Lu, S.; Feng, M.; Lang, J. Outcome of adenoid cystic carcinoma of head and neck after postoperative intensity modulation radiotherapy: A single institution study. Cancer Manag. Res., 2021, 13, 2411-2417.
[http://dx.doi.org/10.2147/CMAR.S283494] [PMID: 33758540]
[6]
Shang, J.; Sheng, L.; Wang, K.; Shui, Y.; Wei, Q. Expression of neural cell adhesion molecule in salivary adenoid cystic carcinoma and its correlation with perineural invasion. Oncol. Rep., 2007, 18(6), 1413-1416.
[http://dx.doi.org/10.3892/or.18.6.1413] [PMID: 17982624]
[7]
Nomura, A.; Majumder, K.; Giri, B.; Dauer, P.; Dudeja, V.; Roy, S.; Banerjee, S.; Saluja, A.K. Inhibition of NF-kappa B pathway leads to deregulation of epithelial-mesenchymal transition and neural invasion in pancreatic cancer. Lab. Invest., 2016, 96(12), 1268-1278.
[http://dx.doi.org/10.1038/labinvest.2016.109] [PMID: 27775688]
[8]
Li, M.; Mukasa, A.; Inda, M.M.; Zhang, J.; Chin, L.; Cavenee, W.; Furnari, F. Guanylate binding protein 1 is a novel effector of EGFR-driven invasion in glioblastoma. J. Exp. Med., 2011, 208(13), 2657-2673.
[http://dx.doi.org/10.1084/jem.20111102] [PMID: 22162832]
[9]
Tabunoki, H.; Saito, N.; Suwanborirux, K.; Charupant, K.; Satoh, J. Molecular network profiling of U373MG human glioblastoma cells following induction of apoptosis by novel marine-derived anti-cancer 1,2,3,4-tetrahydroisoquinoline alkaloids. Cancer Cell Int., 2012, 12(1), 14.
[http://dx.doi.org/10.1186/1475-2867-12-14] [PMID: 22494416]
[10]
Liu, Z.; Jiang, Z.; Huang, J.; Huang, S.; Li, Y.; Yu, S.; Yu, S.; Liu, X. miR-7 inhibits glioblastoma growth by simultaneously interfering with the PI3K/ATK and Raf/MEK/ERK pathways. Int. J. Oncol., 2014, 44(5), 1571-1580.
[http://dx.doi.org/10.3892/ijo.2014.2322] [PMID: 24603851]
[11]
Cantley, L.C. The phosphoinositide 3-kinase pathway. Science, 2002, 296(5573), 1655-1657.
[http://dx.doi.org/10.1126/science.296.5573.1655] [PMID: 12040186]
[12]
Chang, F.; Lee, J.T.; Navolanic, P.M.; Steelman, L.S.; Shelton, J.G.; Blalock, W.L.; Franklin, R.A.; McCubrey, J.A. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: A target for cancer chemotherapy. Leukemia, 2003, 17(3), 590-603.
[http://dx.doi.org/10.1038/sj.leu.2402824] [PMID: 12646949]
[13]
Moule, S.K.; Welsh, G.I.; Edgell, N.J.; Foulstone, E.J.; Proud, C.G.; Denton, R.M. Regulation of protein kinase B and glycogen synthase kinase-3 by insulin and beta-adrenergic agonists in rat epididymal fat cells. Activation of protein kinase B by wortmannin-sensitive and -insensitive mechanisms. J. Biol. Chem., 1997, 272(12), 7713-7719.
[http://dx.doi.org/10.1074/jbc.272.12.7713] [PMID: 9065430]
[14]
Inoki, K.; Li, Y.; Zhu, T.; Wu, J.; Guan, K.L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat. Cell Biol., 2002, 4(9), 648-657.
[http://dx.doi.org/10.1038/ncb839] [PMID: 12172553]
[15]
Clarke, J.; Butowski, N.; Chang, S. Recent advances in therapy for glioblastoma. Arch. Neurol., 2010, 67(3), 279-283.
[http://dx.doi.org/10.1001/archneurol.2010.5] [PMID: 20212224]
[16]
Yang, W.; Xia, Y.; Cao, Y.; Zheng, Y.; Bu, W.; Zhang, L.; You, M.J.; Koh, M.Y.; Cote, G.; Aldape, K.; Li, Y.; Verma, I.M.; Chiao, P.J.; Lu, Z. EGFR-induced and PKCε monoubiquitylation-dependent NF-κB activation upregulates PKM2 expression and promotes tumorigenesis. Mol. Cell, 2012, 48(5), 771-784.
[http://dx.doi.org/10.1016/j.molcel.2012.09.028] [PMID: 23123196]
[17]
Tan, X.; Egami, H.; Ishikawa, S.; Kurizaki, T.; Tamori, Y.; Takai, E.; Hirota, M.; Ogawa, M. Relationship between the expression of extracellular signal-regulated kinase 1/2 and the dissociation of pancreatic cancer cells: Involvement of ERK1/2 in the dissociation status of cancer cells. Int. J. Oncol., 2004, 24(4), 815-820.
[http://dx.doi.org/10.3892/ijo.24.4.815] [PMID: 15010817]
[18]
Du, W.; Pang, C.; Xue, Y.; Zhang, Q.; Wei, X. Dihydroartemisinin inhibits the Raf/ERK/MEK and PI3K/AKT pathways in glioma cells. Oncol. Lett., 2015, 10(5), 3266-3270.
[http://dx.doi.org/10.3892/ol.2015.3699] [PMID: 26722323]
[19]
Kudo-Saito, C.; Shirako, H.; Takeuchi, T.; Kawakami, Y. Cancer metastasis is accelerated through immunosuppression during Snail-induced EMT of cancer cells. Cancer Cell, 2009, 15(3), 195-206.
[http://dx.doi.org/10.1016/j.ccr.2009.01.023] [PMID: 19249678]
[20]
Maeda, M.; Johnson, K.R.; Wheelock, M.J. Cadherin switching: Essential for behavioral but not morphological changes during an epithelium-to-mesenchyme transition. J. Cell Sci., 2005, 118(Pt 5), 873-887.
[http://dx.doi.org/10.1242/jcs.01634] [PMID: 15713751]
[21]
Voulgari, A.; Pintzas, A. Epithelial-mesenchymal transition in cancer metastasis: Mechanisms, markers and strategies to overcome drug resistance in the clinic. Biochim. Biophys. Acta, 2009, 1796(2), 75-90.
[PMID: 19306912]
[22]
Roberts, P.J.; Der, C.J. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene, 2007, 26(22), 3291-3310.
[http://dx.doi.org/10.1038/sj.onc.1210422] [PMID: 17496923]
[23]
Hu, K.; Li, S.L.; Gan, Y.H.; Wang, C.Y.; Yu, G.Y. Epiregulin promotes migration and invasion of salivary adenoid cystic carcinoma cell line SACC-83 through activation of ERK and Akt. Oral Oncol., 2009, 45(2), 156-163.
[http://dx.doi.org/10.1016/j.oraloncology.2008.04.009] [PMID: 18620900]
[24]
Wu, D.M.; Zhao, D.; Li, D.Z.; Xu, D.Y.; Chu, W.F.; Wang, X.F. Maslinic acid induces apoptosis in salivary gland adenoid cystic carcinoma cells by Ca2+-evoked p38 signaling pathway. Naunyn Schmiedebergs Arch. Pharmacol., 2011, 383(3), 321-330.
[http://dx.doi.org/10.1007/s00210-011-0598-x] [PMID: 21279332]
[25]
Hu, J.A.; Li, Y.; Fang, J. Effect of ERK inhibitor on pulmonary metastasis of inoculated human adenoid cystic carcinoma cells in nude mice. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod., 2010, 109(1), 117-123.
[http://dx.doi.org/10.1016/j.tripleo.2009.07.052] [PMID: 20123382]
[26]
Bouaichi, A.; Aimad-Eddine, S.; Mommers, X.A.; Ella, B.; Zwetyenga, N. Intra-mandibular adenoid cystic carcinoma. Rev. Stomatol. Chir. Maxillofac. Chir. Orale, 2014, 115(2), 100-104.
[PMID: 24674932]
[27]
Tagliamento, M.; Rijavec, E.; Barletta, G.; Biello, F.; Rossi, G.; Grossi, F.; Genova, C. CIMAvax-EGF, a therapeutic non-small cell lung cancer vaccine. Expert Opin. Biol. Ther., 2018, 18(7), 829-835.
[http://dx.doi.org/10.1080/14712598.2018.1492539] [PMID: 29936901]
[28]
Hickey, K.; Grehan, D.; Reid, I.M.; O’Briain, S.; Walsh, T.N.; Hennessy, T.P. Expression of epidermal growth factor receptor and proliferating cell nuclear antigen predicts response of esophageal squamous cell carcinoma to chemoradiotherapy. Cancer, 1994, 74(6), 1693-1698.
[http://dx.doi.org/10.1002/1097-0142(19940915)74:6<1693:AID-CNCR2820740609>3.0.CO;2-#] [PMID: 7915963]
[29]
Ding, Z.; Roos, A.; Kloss, J.; Dhruv, H.; Peng, S.; Pirrotte, P.; Eschbacher, J.M.; Tran, N.L.; Loftus, J.C. A novel signaling complex between TROY and EGFR mediates glioblastoma cell invasion. Mol. Cancer Res., 2018, 16(2), 322-332.
[http://dx.doi.org/10.1158/1541-7786.MCR-17-0454] [PMID: 29117939]
[30]
McCarthy, S.A.; Samuels, M.L.; Pritchard, C.A.; Abraham, J.A.; McMahon, M. Rapid induction of heparin-binding epidermal growth factor/diphtheria toxin receptor expression by Raf and Ras oncogenes. Genes Dev., 1995, 9(16), 1953-1964.
[http://dx.doi.org/10.1101/gad.9.16.1953] [PMID: 7649477]
[31]
Taylor, B.S.; Schultz, N.; Hieronymus, H.; Gopalan, A.; Xiao, Y.; Carver, B.S.; Arora, V.K.; Kaushik, P.; Cerami, E.; Reva, B.; Antipin, Y.; Mitsiades, N.; Landers, T.; Dolgalev, I.; Major, J.E.; Wilson, M.; Socci, N.D.; Lash, A.E.; Heguy, A.; Eastham, J.A.; Scher, H.I.; Reuter, V.E.; Scardino, P.T.; Sander, C.; Sawyers, C.L.; Gerald, W.L. Integrative genomic profiling of human prostate cancer. Cancer Cell, 2010, 18(1), 11-22.
[http://dx.doi.org/10.1016/j.ccr.2010.05.026] [PMID: 20579941]
[32]
Danielsen, S.A.; Eide, P.W.; Nesbakken, A.; Guren, T.; Leithe, E.; Lothe, R.A. Portrait of the PI3K/AKT pathway in colorectal cancer. Biochim. Biophys. Acta, 2015, 1855(1), 104-121.
[PMID: 25450577]
[33]
Henderson, V.; Smith, B.; Burton, L.J.; Randle, D.; Morris, M.; Odero-Marah, V.A. Snail promotes cell migration through PI3K/AKT-dependent Rac1 activation as well as PI3K/AKT-independent pathways during prostate cancer progression. Cell Adhes. Migr., 2015, 9(4), 255-264.
[http://dx.doi.org/10.1080/19336918.2015.1013383] [PMID: 26207671]
[34]
Wykosky, J.; Hu, J.; Gomez, G.G.; Taylor, T.; Villa, G.R.; Pizzo, D.; VandenBerg, S.R.; Thorne, A.H.; Chen, C.C.; Mischel, P.S.; Gonias, S.L.; Cavenee, W.K.; Furnari, F.B. A urokinase receptor-Bim signaling axis emerges during EGFR inhibitor resistance in mutant EGFR glioblastoma. Cancer Res., 2015, 75(2), 394-404.
[http://dx.doi.org/10.1158/0008-5472.CAN-14-2004] [PMID: 25432173]
[35]
Pi, J.; Jiang, J.; Cai, H.; Yang, F.; Jin, H.; Yang, P.; Cai, J.; Chen, Z.W. GE11 peptide conjugated selenium nanoparticles for EGFR targeted oridonin delivery to achieve enhanced anticancer efficacy by inhibiting EGFR-mediated PI3K/AKT and Ras/Raf/MEK/ERK pathways. Drug Deliv., 2017, 24(1), 1549-1564.
[http://dx.doi.org/10.1080/10717544.2017.1386729] [PMID: 29019267]
[36]
Hoeflich, K.P.; O’Brien, C.; Boyd, Z.; Cavet, G.; Guerrero, S.; Jung, K.; Januario, T.; Savage, H.; Punnoose, E.; Truong, T.; Zhou, W.; Berry, L.; Murray, L.; Amler, L.; Belvin, M.; Friedman, L.S.; Lackner, M.R. In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models. Clin. Cancer Res., 2009, 15(14), 4649-4664.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-0317] [PMID: 19567590]
[37]
Mirzoeva, O.K.; Das, D.; Heiser, L.M.; Bhattacharya, S.; Siwak, D.; Gendelman, R.; Bayani, N.; Wang, N.J.; Neve, R.M.; Guan, Y.; Hu, Z.; Knight, Z.; Feiler, H.S.; Gascard, P.; Parvin, B.; Spellman, P.T.; Shokat, K.M.; Wyrobek, A.J.; Bissell, M.J.; McCormick, F.; Kuo, W.L.; Mills, G.B.; Gray, J.W.; Korn, W.M. Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition. Cancer Res., 2009, 69(2), 565-572.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-3389] [PMID: 19147570]
[38]
Alessi, D.R.; Cuenda, A.; Cohen, P.; Dudley, D.T.; Saltiel, A.R. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J. Biol. Chem., 1995, 270(46), 27489-27494.
[http://dx.doi.org/10.1074/jbc.270.46.27489] [PMID: 7499206]
[39]
Sheppard, K.E.; Cullinane, C.; Hannan, K.M.; Wall, M.; Chan, J.; Barber, F.; Foo, J.; Cameron, D.; Neilsen, A.; Ng, P.; Ellul, J.; Kleinschmidt, M.; Kinross, K.M.; Bowtell, D.D.; Christensen, J.G.; Hicks, R.J.; Johnstone, R. W.; McArthur, G.A.; Hannan, R.D.; Phillips, W.A.; Pearson, R.B. Synergistic inhibition of ovarian cancer cell growth by combining selective PI3K/mTOR and RAS/ERK pathway inhibitors. Eur. J. Cancer. (Oxford, England: 1990), 2013, 49(18), 3936-3944.
[40]
Wang, Y.; Hu, J.; Wang, Y.; Ye, W.; Zhang, X.; Ju, H.; Xu, D.; Liu, L.; Ye, D.; Zhang, L.; Zhu, D.; Deng, J.; Zhang, Z.; Liu, S. EGFR activation induced Snail-dependent EMT and myc-dependent PD-L1 in human salivary adenoid cystic carcinoma cells. Cell Cycle, 2018, 17(12), 1457-1470.
[http://dx.doi.org/10.1080/15384101.2018.1489177] [PMID: 29954240]

Rights & Permissions Print Cite
Article Metrics
23
1
© 2024 Bentham Science Publishers | Privacy Policy