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Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Thymoquinone Inhibits Proliferation and Migration of MDA-MB-231 Triple Negative Breast Cancer Cells by Suppressing Autophagy, Beclin-1 and LC3

Author(s): Tuba D. Ünal, Zuhal Hamurcu, Nesrin Delibaşı, Venhar Çınar, Ahsen Güler, Sevda Gökçe, Nursultan Nurdinov and Bulent Ozpolat*

Volume 21 , Issue 3 , 2021

Published on: 07 August, 2020

Page: [355 - 364] Pages: 10

DOI: 10.2174/1871520620666200807221047

Price: $65

Abstract

Background: Triple Negative Breast Cancer (TNBC) is an aggressive and highly heterogeneous subtype of breast cancer associated with poor prognosis. A better understanding of the biology of this complex cancer is needed to develop novel therapeutic strategies for the improvement of patient survival. We have previously demonstrated that Thymoquinone (TQ), the major phenolic compound found in Nigella sativa, induces anti-proliferative and anti-metastatic effects and inhibits in vivo tumor growth in orthotopic TNBC models in mice. Also, we have previously shown that Beclin-1 and LC3 autophagy genes contributes to TNBC cell proliferation, migration and invasion, suggesting that Beclin-1 and LC3 genes provide proto-oncogenic effects in TNBC. However, the role of Beclin-1 and LC3 in mediating TQ-induced anti-tumor effects in TNBC is not known.

Objective: To investigate the effects of TQ on the major autophagy mediators, Beclin-1 and LC3 expression, as well as autophagic activity in TNBC cells.

Methods: Cell proliferation, colony formation, migration and autophagy activity were evaluated using MTS cell viability, colony formation assay, wound healing and acridine orange staining assays, respectively. Western blotting and RT-PCR assays were used to investigate LC3 and Beclin-1 protein and gene expressions, respectively, in MDA-MB-231 TNBC cells in response to TQ treatments.

Results: TQ treatment significantly inhibited cell proliferation, colony formation, migration and autophagic activity of MDA-MB-231 cells and suppressed LC3 and Beclin-1 expressions. Furthermore, TQ treatment led to the inhibition of Integrin-β1, VEGF, MMP-2 and MMP-9 in TNBC cells.

Conclusion: TQ inhibits autophagic activity and expression of Beclin-1 and LC3 in TNBC cells and suppresses pathways related to cell migration/invasion and angiogenesis, including Integrin-β1, VEGF, MMP-2 and MMP- 9, suggesting that TQ may be used to control autophagic activity and oncogenic signaling in TNBC.

Keywords: Thymoquinone, autophagy, Nigella sativa, LC3, Beclin-1, Integrin-β1, VEGF, MMP-2, MMP-9, breast cancer, treatment, invasion, angiogenesis.

Graphical Abstract
[1]
Cao, W.; Li, J.; Hao, Q.; Vadgama, J.V.; Wu, Y. AMP-activated protein kinase: A potential therapeutic target for triple-negative breast cancer. Breast Cancer Res., 2019, 21(1), 29.
[http://dx.doi.org/10.1186/s13058-019-1107-2] [PMID: 30791936]
[2]
Gandhi, N.; Das, G.M. Metabolic reprogramming in breast cancer and its therapeutic implications. Cells, 2019, 8(2), 89.
[http://dx.doi.org/10.3390/cells8020089] [PMID: 30691108]
[3]
Schmid, P.; Adams, S.; Rugo, H.S.; Schneeweiss, A.; Barrios, C.H.; Iwata, H.; Diéras, V.; Hegg, R. Im, S.A.; Shaw Wright, G.; Henschel, V.; Molinero, L.; Chui, S.Y.; Funke, R.; Husain, A.; Winer, E.P.; Loi, S.; Emens, L.A. IMpassion130 trial investigators. atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N. Engl. J. Med., 2018, 379(22), 2108-2121.
[http://dx.doi.org/10.1056/NEJMoa1809615] [PMID: 30345906]
[4]
Bardia, A.; Mayer, I.A.; Vahdat, L.T.; Tolaney, S.M.; Isakoff, S.J.; Diamond, J.R.; O’Shaughnessy, J.; Moroose, R.L.; Santin, A.D.; Abramson, V.G.; Shah, N.C.; Rugo, H.S.; Goldenberg, D.M.; Sweidan, A.M.; Iannone, R.; Washkowitz, S.; Sharkey, R.M.; Wegener, W.A.; Kalinsky, K. Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N. Engl. J. Med., 2019, 380(8), 741-751.
[http://dx.doi.org/10.1056/NEJMoa1814213] [PMID: 30786188]
[5]
Glick, D.; Barth, S.; Macleod, K.F. Autophagy: Cellular and molecular mechanisms. J. Pathol., 2010, 221(1), 3-12.
[http://dx.doi.org/10.1002/path.2697] [PMID: 20225336]
[6]
Dalby, K.N.; Tekedereli, I.; Lopez-Berestein, G.; Ozpolat, B. Targeting the prodeath and prosurvival functions of autophagy as novel therapeutic strategies in cancer. Autophagy, 2010, 6(3), 322-329.
[http://dx.doi.org/10.4161/auto.6.3.11625] [PMID: 20224296]
[7]
Ozpolat, B.; Benbrook, D.M. Targeting autophagy in cancer management - strategies and developments. Cancer Manag. Res., 2015, 7, 291-299.
[http://dx.doi.org/10.2147/CMAR.S34859] [PMID: 26392787]
[8]
Lazova, R.; Camp, R.L.; Klump, V.; Siddiqui, S.F.; Amaravadi, R.K.; Pawelek, J.M. Punctate LC3B expression is a common feature of solid tumors and associated with proliferation, metastasis, and poor outcome. Clin. Cancer Res., 2012, 18(2), 370-379.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-1282] [PMID: 22080440]
[9]
Zhao, H.; Yang, M.; Zhao, J.; Wang, J.; Zhang, Y.; Zhang, Q. High expression of LC3B is associated with progression and poor outcome in triple-negative breast cancer. Med. Oncol., 2013, 30(1), 475.
[http://dx.doi.org/10.1007/s12032-013-0475-1] [PMID: 23371253]
[10]
Deng, S.; Shanmugam, M.K.; Kumar, A.P.; Yap, C.T.; Sethi, G.; Bishayee, A. Targeting autophagy using natural compounds for cancer prevention and therapy. Cancer, 2019, 125(8), 1228-1246.
[http://dx.doi.org/10.1002/cncr.31978] [PMID: 30748003]
[11]
Hamurcu, Z.; Delibaşı, N.; Geçene, S.; Şener, E.F.; Dönmez-Altuntaş, H.; Özkul, Y.; Canatan, H.; Ozpolat, B. Targeting LC3 and Beclin-1 autophagy genes suppresses proliferation, survival, migration and invasion by inhibition of Cyclin-D1 and uPAR/Integrin β1/Src signaling in triple negative breast cancer cells. J. Cancer Res. Clin. Oncol., 2018, 144(3), 415-430.
[http://dx.doi.org/10.1007/s00432-017-2557-5] [PMID: 29288363]
[12]
Chowdhury, F.A.; Hossain, M.K.; Mostofa, A.G.M.; Akbor, M.M.; Bin Sayeed, M.S. Therapeutic potential of thymoquinone in glioblastoma treatment: Targeting major gliomagenesis signaling pathways. BioMed Res. Int., 2018, 20184010629
[http://dx.doi.org/10.1155/2018/4010629]] [PMID: 29651429]
[13]
Rajput, S.; Puvvada, N.; Kumar, B.N.; Sarkar, S.; Konar, S.; Bharti, R.; Dey, G.; Mazumdar, A.; Pathak, A.; Fisher, P.B.; Mandal, M. Overcoming Akt induced therapeutic resistance in breast cancer through siRNA and thymoquinone encapsulated multilamellar gold niosomes. Mol. Pharm., 2015, 12(12), 4214-4225.
[http://dx.doi.org/10.1021/acs.molpharmaceut.5b00692] [PMID: 26505213]
[14]
El-Mahdy, M.A.; Zhu, Q.; Wang, Q.E.; Wani, G.; Wani, A.A. Thymoquinone induces apoptosis through activation of caspase-8 and mitochondrial events in p53-null myeloblastic leukemia HL-60 cells. Int. J. Cancer, 2005, 117(3), 409-417.
[http://dx.doi.org/10.1002/ijc.21205] [PMID: 15906362]
[15]
Yang, J.; Kuang, X.R.; Lv, P.T.; Yan, X.X. Thymoquinone inhibits proliferation and invasion of human nonsmall-cell lung cancer cells via ERK pathway. Tumour Biol., 2015, 36(1), 259-269.
[http://dx.doi.org/10.1007/s13277-014-2628-z] [PMID: 25238880]
[16]
Khalife, R.; Hodroj, M.H.; Fakhoury, R.; Rizk, S. Thymoquinone from Nigella sativa seeds promotes the antitumor activity of noncytotoxic doses of topotecan in human colorectal cancer cells in vitro. Planta Med., 2016, 82(4), 312-321.
[http://dx.doi.org/10.1055/s-0035-1558289] [PMID: 26848703]
[17]
Banerjee, S.; Kaseb, A.O.; Wang, Z.; Kong, D.; Mohammad, M.; Padhye, S.; Sarkar, F.H.; Mohammad, R.M. Antitumor activity of gemcitabine and oxaliplatin is augmented by thymoquinone in pancreatic cancer. Cancer Res., 2009, 69(13), 5575-5583.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-4235] [PMID: 19549912]
[18]
Ozturk, S.A.; Alp, E.; Yar Saglam, A.S.; Konac, E.; Menevse, E.S. The effects of thymoquinone and genistein treatment on telomerase activity, apoptosis, angiogenesis, and survival in thyroid cancer cell lines. J. Cancer Res. Ther., 2018, 14(2), 328-334.
[PMID: 29516914]
[19]
Roepke, M.; Diestel, A.; Bajbouj, K.; Walluscheck, D.; Schonfeld, P.; Roessner, A.; Schneider-Stock, R.; Gali-Muhtasib, H. Lack of p53 augments thymoquinone-induced apoptosis and caspase activation in human osteosarcoma cells. Cancer Biol. Ther., 2007, 6(2), 160-169.
[http://dx.doi.org/10.4161/cbt.6.2.3575] [PMID: 17218778]
[20]
Kou, B.; Liu, W.; Zhao, W.; Duan, P.; Yang, Y.; Yi, Q.; Guo, F.; Li, J.; Zhou, J.; Kou, Q. Thymoquinone inhibits epithelial-mesenchymal transition in prostate cancer cells by negatively regulating the TGF-β/Smad2/3 signaling pathway. Oncol. Rep., 2017, 38(6), 3592-3598.
[http://dx.doi.org/10.3892/or.2017.6012] [PMID: 29039572]
[21]
Chu, S.C.; Hsieh, Y.S.; Yu, C.C.; Lai, Y.Y.; Chen, P.N. Thymoquinone induces cell death in human squamous carcinoma cells via caspase activation-dependent apoptosis and LC3-II activation-dependent autophagy. PLoS One, 2014, 9(7)e101579
[22]
Chen, M.C.; Lee, N.H.; Hsu, H.H.; Ho, T.J.; Tu, C.C.; Hsieh, D.J.; Lin, Y.M.; Chen, L.M.; Kuo, W.W.; Huang, C.Y. Thymoquinone induces caspase-independent, autophagic cell death in CPT-11-resistant lovo colon cancer via mitochondrial dysfunction and activation of JNK and p38. J. Agric. Food Chem., 2015, 63(5), 1540-1546.
[http://dx.doi.org/10.1021/jf5054063] [PMID: 25611974]
[23]
Zhang, Y.; Fan, Y.; Huang, S.; Wang, G.; Han, R.; Lei, F.; Luo, A.; Jing, X.; Zhao, L.; Gu, S.; Zhao, X. Thymoquinone inhibits the metastasis of renal cell cancer cells by inducing autophagy via AMPK/mTOR signaling pathway. Cancer Sci., 2018, 109(12), 3865-3873.
[http://dx.doi.org/10.1111/cas.13808] [PMID: 30259603]
[24]
Bashmail, H.A.; Alamoudi, A.A.; Noorwali, A.; Hegazy, G.A. AJabnoor, G.; Choudhry, H.; Al-Abd, A.M. Thymoquinone synergizes gemcitabine anti-breast cancer activity via modulating its apoptotic and autophagic activities. Sci. Rep., 2018, 8(1), 11674.
[http://dx.doi.org/10.1038/s41598-018-30046-z] [PMID: 30076320]
[25]
Pazhouhi, M.; Sariri, R.; Rabzia, A.; Khazaei, M. Thymoquinone synergistically potentiates temozolomide cytotoxicity through the inhibition of autophagy in U87MG cell line. Iran. J. Basic Med. Sci., 2016, 19(8), 890-898.
[PMID: 27746872]
[26]
Racoma, I.O.; Meisen, W.H.; Wang, Q.E.; Kaur, B.; Wani, A.A. Thymoquinone inhibits autophagy and induces cathepsin-mediated, caspase-independent cell death in glioblastoma cells. PLoS One, 2013, 8(9)e72882
[http://dx.doi.org/10.1371/journal.pone.0072882]] [PMID: 24039814]
[27]
Kabil, N.; Bayraktar, R.; Kahraman, N.; Mokhlis, H.A.; Calin, G.A.; Lopez-Berestein, G.; Ozpolat, B. Thymoquinone inhibits cell proliferation, migration, and invasion by regulating the Elongation Factor 2 Kinase (eEF-2K) signaling axis in triple-negative breast cancer. Breast Cancer Res. Treat., 2018, 171(3), 593-605.
[http://dx.doi.org/10.1007/s10549-018-4847-2] [PMID: 29971628]
[28]
Mizushima, N.; Yoshimori, T.; Levine, B. Methods in mammalian autophagy research. Cell, 2010, 140(3), 313-326.
[http://dx.doi.org/10.1016/j.cell.2010.01.028] [PMID: 20144757]
[29]
Redmann, M.; Benavides, G.A.; Berryhill, T.F.; Wani, W.Y.; Ouyang, X.; Johnson, M.S.; Ravi, S.; Barnes, S.; Darley-Usmar, V.M.; Zhang, J. Inhibition of autophagy with bafilomycin and chloroquine decreases mitochondrial quality and bioenergetic function in primary neurons. Redox Biol., 2017, 11, 73-81.
[http://dx.doi.org/10.1016/j.redox.2016.11.004] [PMID: 27889640]
[30]
Hamurcu, Z.; Delibaşı, N.; Nalbantoglu, U.; Sener, E.F.; Nurdinov, N.; Tascı, B.; Taheri, S.; Özkul, Y.; Donmez-Altuntas, H.; Canatan, H.; Ozpolat, B. FOXM1 plays a role in autophagy by transcriptionally regulating Beclin-1 and LC3 genes in human triple-negative breast cancer cells. J. Mol. Med. (Berl.), 2019, 97(4), 491-508.
[http://dx.doi.org/10.1007/s00109-019-01750-8] [PMID: 30729279]
[31]
Yoshii, S.R.; Mizushima, N. Monitoring and measuring autophagy. Int. J. Mol. Sci., 2017, 18(9), 1865.
[http://dx.doi.org/10.3390/ijms18091865] [PMID: 28846632]
[32]
Orhon, I.; Reggiori, F. Assays to monitor autophagy progression in cell cultures. Cells, 2017, 6(3), 20.
[http://dx.doi.org/10.3390/cells6030020] [PMID: 28686195]
[33]
Klionsky, D.J.; Abdelmohsen, K.; Abe, A.; Abedin, M.J.; Abeliovich, H.; Acevedo Arozena, A.; Adachi, H.; Adams, C.M.; Adams, P.D.; Adeli, K.; Adhihetty, P.J.; Adler, S.G.; Agam, G.; Agarwal, R.; Aghi, M.K.; Agnello, M.; Agostinis, P.; Aguilar, P.V.; Aguirre-Ghiso, J.; Airoldi, E.M.; Ait-Si-Ali, S. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy, 2016, 12, 1-222.
[34]
Pasquier, B. SAR405, a PIK3C3/Vps34 inhibitor that prevents autophagy and synergizes with MTOR inhibition in tumor cells. Autophagy, 2015, 11(4), 725-726.
[http://dx.doi.org/10.1080/15548627.2015.1033601] [PMID: 25905679]
[35]
Katsuyuki, K.; Takao, M.; Haruhiko, S.; Akihiko, M.; Tomoki, N.; Akihiro, S.; Hiroaki, M.; Shigekuni, H.; Nicola, B. Intraoperative Photodynamic Surgery (iPDS) with acridine orange for musculoskeletal sarcomas. Cureus, 2014, 6e204
[36]
Tekedereli, I.; Alpay, S.N.; Tavares, C.D.; Cobanoglu, Z.E.; Kaoud, T.S.; Sahin, I.; Sood, A.K.; Lopez-Berestein, G.; Dalby, K.N.; Ozpolat, B. Targeted silencing of elongation factor 2 kinase suppresses growth and sensitizes tumors to doxorubicin in an orthotopic model of breast cancer. PLoS One, 2012, 7(7)e41171
[http://dx.doi.org/10.1371/journal.pone.0041171]] [PMID: 22911754]
[37]
Akar, U.; Chaves-Reyez, A.; Barria, M.; Tari, A.; Sanguino, A.; Kondo, Y.; Kondo, S.; Arun, B.; Lopez-Berestein, G.; Ozpolat, B. Silencing of Bcl-2 expression by small interfering RNA induces autophagic cell death in MCF-7 breast cancer cells. Autophagy, 2008, 4(5), 669-679.
[http://dx.doi.org/10.4161/auto.6083] [PMID: 18424910]
[38]
Klahan, S.; Huang, W.C.; Chang, C.M.; Wong, H.S.; Huang, C.C.; Wu, M.S.; Lin, Y.C.; Lu, H.F.; Hou, M.F.; Chang, W.C. Gene expression profiling combined with functional analysis Identify Integrin Beta1 (ITGB1) as a potential prognosis biomarker in triple negative breast cancer. Pharmacol. Res., 2016, 104, 31-37.
[http://dx.doi.org/10.1016/j.phrs.2015.12.004] [PMID: 26675717]
[39]
Pan, B.; Guo, J.; Liao, Q.; Zhao, Y. β1 and β3 integrins in breast, prostate and pancreatic cancer: A novel implication. Oncol. Lett., 2018, 15(4), 5412-5416.
[http://dx.doi.org/10.3892/ol.2018.8076] [PMID: 29556293]
[40]
Hamurcu, Z.; Kahraman, N.; Ashour, A.; Ozpolat, B. FOXM1 transcriptionally regulates expression of integrin β1 in triple-negative breast cancer. Breast Cancer Res. Treat., 2017, 163(3), 485-493.
[http://dx.doi.org/10.1007/s10549-017-4207-7] [PMID: 28361350]
[41]
Chi, Y.; Huang, S.; Peng, H.; Liu, M.; Zhao, J.; Shao, Z.; Wu, J. Critical role of CDK11(p58) in human breast cancer growth and angiogenesis. BMC Cancer, 2015, 15, 701.
[http://dx.doi.org/10.1186/s12885-015-1698-7] [PMID: 26470709]
[42]
Varinska, L.; Gal, P.; Mojzisova, G.; Mirossay, L.; Mojzis, J. Soy and breast cancer: Focus on angiogenesis. Int. J. Mol. Sci., 2015, 16(5), 11728-11749.
[http://dx.doi.org/10.3390/ijms160511728] [PMID: 26006245]
[43]
Farkhondeh, T.; Samarghandian, S.; Hozeifi, S.; Azimi-Nezhad, M. Therapeutic effects of thymoquinone for the treatment of central nervous system tumors: A review. Biomed. Pharmacother., 2017, 96, 1440-1444.
[http://dx.doi.org/10.1016/j.biopha.2017.12.013] [PMID: 29223556]
[44]
Majdalawieh, A.F.; Fayyad, M.W.; Nasrallah, G.K. Anti-cancer properties and mechanisms of action of thymoquinone, the major active ingredient of Nigella sativa. Crit. Rev. Food Sci. Nutr., 2017, 57(18), 3911-3928.
[http://dx.doi.org/10.1080/10408398.2016.1277971] [PMID: 28140613]
[45]
Bashmail, H.A.; Alamoudi, A.A.; Noorwali, A.; Hegazy, G.A.; Ajabnoor, G.M.; Al-Abd, A.M. Thymoquinone enhances paclitaxel anti-breast cancer activity via inhibiting tumor-associated stem cells despite apparent mathematical antagonism. Molecules, 2020, 25(2), 426.
[http://dx.doi.org/10.3390/molecules25020426] [PMID: 31968657]
[46]
Maycotte, P.; Thorburn, A. Targeting autophagy in breast cancer. World J. Clin. Oncol., 2014, 5(3), 224-240.
[http://dx.doi.org/10.5306/wjco.v5.i3.224] [PMID: 25114840]
[47]
Elmaci, I.; Altinoz, M.A. Thymoquinone: An edible redox-active quinone for the pharmacotherapy of neurodegenerative conditions and glial brain tumors. A short review. Biomed. Pharmacother., 2016, 83, 635-640.
[http://dx.doi.org/10.1016/j.biopha.2016.07.018] [PMID: 27459120]
[48]
Lefort, S.; Joffre, C.; Kieffer, Y.; Givel, A.M.; Bourachot, B.; Zago, G.; Bieche, I.; Dubois, T.; Meseure, D.; Vincent-Salomon, A.; Camonis, J.; Mechta-Grigoriou, F. Inhibition of autophagy as a new means of improving chemotherapy efficiency in high-LC3B triple-negative breast cancers. Autophagy, 2014, 10(12), 2122-2142.
[http://dx.doi.org/10.4161/15548627.2014.981788] [PMID: 25427136]
[49]
Jung, Y.Y.; Lee, Y.K.; Koo, J.S. The potential of Beclin 1 as a therapeutic target for the treatment of breast cancer. Expert Opin. Ther. Targets, 2016, 20(2), 167-178.
[http://dx.doi.org/10.1517/14728222.2016.1085971] [PMID: 26357854]
[50]
Zhang, F.; Wang, B.; Long, H.; Yu, J.; Li, F.; Hou, H.; Yang, Q. Decreased miR-124-3p expression prompted breast cancer cell progression mainly by targeting Beclin-1. Clin. Lab., 2016, 62(6), 1139-1145.
[http://dx.doi.org/10.7754/Clin.Lab.2015.151111] [PMID: 27468577]
[51]
Das, V.; Kalyan, G.; Hazra, S.; Pal, M. Understanding the role of structural integrity and differential expression of integrin profiling to identify potential therapeutic targets in breast cancer. J. Cell. Physiol., 2018, 233(1), 168-185.
[http://dx.doi.org/10.1002/jcp.25821] [PMID: 28120356]
[52]
Jahangiri, A.; Aghi, M.K.; Carbonell, W.S. β1 integrin: Critical path to antiangiogenic therapy resistance and beyond. Cancer Res., 2014, 74(1), 3-7.
[http://dx.doi.org/10.1158/0008-5472.CAN-13-1742] [PMID: 24327727]
[53]
Ashour, A.A.; Gurbuz, N.; Alpay, S.N.; Abdel-Aziz, A.A.; Mansour, A.M.; Huo, L.; Ozpolat, B. Elongation factor-2 kinase regulates TG2/β1 integrin/Src/uPAR pathway and epithelial-mesenchymal transition mediating pancreatic cancer cells invasion. J. Cell. Mol. Med., 2014, 18(11), 2235-2251.
[http://dx.doi.org/10.1111/jcmm.12361] [PMID: 25215932]
[54]
Yin, H.L.; Wu, C.C.; Lin, C.H.; Chai, C.Y.; Hou, M.F.; Chang, S.J.; Tsai, H.P.; Hung, W.C.; Pan, M.R.; Luo, C.W. β1 Integrin as a prognostic and predictive marker in triple-negative breast cancer. Int. J. Mol. Sci., 2016, 17(9), 1432.
[http://dx.doi.org/10.3390/ijms17091432] [PMID: 27589736]
[55]
Huang, Y.T.; Zhao, L.; Fu, Z.; Zhao, M.; Song, X.M.; Jia, J.; Wang, S.; Li, J.P.; Zhu, Z.F.; Lin, G.; Lu, R.; Yao, Z. Therapeutic effects of tyroservatide on metastasis of lung cancer and its mechanism affecting integrin-focal adhesion kinase signal transduction. Drug Des. Devel. Ther., 2016, 10, 649-663.
[PMID: 27041993]
[56]
Liu, C.; Qu, L.; Zhao, C.; Shou, C. Extracellular gamma-synuclein promotes tumor cell motility by activating β1 integrin-focal adhesion kinase signaling pathway and increasing matrix metalloproteinase-24, -2 protein secretion. J. Exp. Clin. Cancer Res., 2018, 37(1), 117.
[http://dx.doi.org/10.1186/s13046-018-0783-6] [PMID: 29903032]
[57]
Jeong, B.Y.; Cho, K.H.; Jeong, K.J.; Park, Y.Y.; Kim, J.M.; Rha, S.Y.; Park, C.G.; Mills, G.B.; Cheong, J.H.; Lee, H.Y. Author Correction: Rab25 augments cancer cell invasiveness through a β1 integrin/EGFR/VEGF-A/Snail signaling axis and expression of fascin. Exp. Mol. Med., 2018, 50(9), 124.
[http://dx.doi.org/10.1038/s12276-018-0148-4] [PMID: 30232331]
[58]
Peng, L.; Liu, A.; Shen, Y.; Xu, H.Z.; Yang, S.Z.; Ying, X.Z.; Liao, W.; Liu, H.X.; Lin, Z.Q.; Chen, Q.Y.; Cheng, S.W.; Shen, W.D. Antitumor and anti-angiogenesis effects of thymoquinone on osteosarcoma through the NF-κB pathway. Oncol. Rep., 2013, 29(2), 571-578.
[http://dx.doi.org/10.3892/or.2012.2165] [PMID: 23232982]
[59]
Yi, T.; Cho, S.G.; Yi, Z.; Pang, X.; Rodriguez, M.; Wang, Y.; Sethi, G.; Aggarwal, B.B.; Liu, M. Thymoquinone inhibits tumor angiogenesis and tumor growth through suppressing AKT and extracellular signal-regulated kinase signaling pathways. Mol. Cancer Ther., 2008, 7(7), 1789-1796.
[http://dx.doi.org/10.1158/1535-7163.MCT-08-0124] [PMID: 18644991]

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