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Anti-Cancer Agents in Medicinal Chemistry

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

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Research Article

Down-Regulation of DDR1 Induces Apoptosis and Inhibits EMT through Phosphorylation of Pyk2/MKK7 in DU-145 and Lncap-FGC Prostate Cancer Cell Lines

Author(s): Reza Azizi, Faranak Fallahian, Mahmoud Aghaei* and Zahra Salemi

Volume 20, Issue 8, 2020

Page: [1009 - 1016] Pages: 8

DOI: 10.2174/1871520620666200410075558

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Abstract

Background: In cancer cells, re-activation of Epithelial-Mesenchymal Transition (EMT) program through Discoidin Domain Receptor1 (DDR1) leads to metastasis. DDR1-targeted therapy with siRNA might be a promising strategy for EMT inhibition. Therefore, the aim of this study was to investigate the effect of DDR1 knockdown in the EMT, migration, and apoptosis of prostate cancer cells. For this purpose, the expression of DDR1 was down regulated by the siRNA approach in LNcap-FGC and DU-145 prostate cancer cells.

Methods: Immunocytochemistry was carried out for the assessment of EMT. E-cadherin, N-cadherin, Bax, Bcl2, and the phosphorylation level of Proline-rich tyrosine kinase 2 (Pyk2) and Map Kinase Kinase 7 (MKK7) was determined using the western blot. Wound healing assay was used to evaluate cell migration. Flow cytometry was employed to determine the apoptosis rate in siRNA-transfected cancer cells.

Results: Our findings showed that the stimulation of DDR1 with collagen-I caused increased phosphorylation of Pyk2 and MKK7 signaling molecules that led to the induction of EMT and migration in DU-145 and LNcap- FGC cells. In contrast, DDR1 knockdown led to significant attenuation of EMT, migration, and phosphorylation levels of Pyk2 and MKK7. Moreover, DDR1 knockdown via induction of Bax expression and suppression of Bcl-2 expression induces apoptosis.

Conclusion: Collectively, our results indicate that the DDR1 targeting with siRNA may be beneficial for the inhibition of EMT and the induction of apoptosis in prostate cancer.

Keywords: Discoidin domain receptor 1 (DDR1), epithelial-mesenchymal transition (EMT), small interfering RNA, apoptosis, MKK7, Pyk2.

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[1]
Thiery, J.P. Epithelial-mesenchymal transitions in tumour progression. Nat. Rev. Cancer, 2002, 2(6), 442-454.
[http://dx.doi.org/10.1038/nrc822] [PMID: 12189386]
[2]
Brabletz, T.; Kalluri, R.; Nieto, M.A.; Weinberg, R.A. EMT in cancer. Nat. Rev. Cancer, 2018, 18(2), 128-134.
[http://dx.doi.org/10.1038/nrc.2017.118] [PMID: 29326430]
[3]
Rosado, P.; Lequerica-Fernández, P.; Fernández, S.; Allonca, E.; Villallaín, L.; de Vicente, J.C. E-cadherin and β-catenin expression in well-differentiated and moderately-differentiated oral squamous cell carcinoma: relations with clinical variables. Br. J. Oral Maxillofac. Surg., 2013, 51(2), 149-156.
[http://dx.doi.org/10.1016/j.bjoms.2012.03.018] [PMID: 22525043]
[4]
Wang, M.; Ren, D.; Guo, W.; Huang, S.; Wang, Z.; Li, Q.; Du, H.; Song, L.; Peng, X. N-cadherin promotes epithelial-mesenchymal transition and cancer stem cell-like traits via ErbB signaling in prostate cancer cells. Int. J. Oncol., 2016, 48(2), 595-606.
[http://dx.doi.org/10.3892/ijo.2015.3270] [PMID: 26647992]
[5]
Satelli, A.; Li, S. Vimentin in cancer and its potential as a molecular target for cancer therapy. Cell. Mol. Life Sci., 2011, 68(18), 3033-3046.
[http://dx.doi.org/10.1007/s00018-011-0735-1] [PMID: 21637948]
[6]
Brzozowa, M.; Wyrobiec, G.; Kołodziej, I.; Sitarski, M.; Matysiak, N.; Reichman-Warmusz, E.; Żaba, M.; Wojnicz, R. The aberrant overexpression of vimentin is linked to a more aggressive status in tumours of the gastrointestinal tract. Prz. Gastroenterol., 2015, 10(1), 7-11.
[http://dx.doi.org/10.5114/pg.2014.47502] [PMID: 25960808]
[7]
Thiery, J.P.; Acloque, H.; Huang, R.Y.; Nieto, M.A. Epithelial-mesenchymal transitions in development and disease. Cell, 2009, 139(5), 871-890.
[8]
Khan, M.I.; Hamid, A.; Adhami, V.M.; Lall, R.K.; Mukhtar, H. Role of epithelial mesenchymal transition in prostate tumorigenesis. Curr. Pharm. Des., 2015, 21(10), 1240-1248.
[http://dx.doi.org/10.2174/1381612821666141211120326] [PMID: 25506896]
[9]
Slabáková, E.; Pernicová, Z.; Slavíčková, E.; Staršíchová, A.; Kozubík, A.; Souček, K. TGF-β1-induced EMT of non-transformed prostate hyperplasia cells is characterized by early induction of SNAI2/Slug. Prostate, 2011, 71(12), 1332-1343.
[http://dx.doi.org/10.1002/pros.21350] [PMID: 21321977]
[10]
Chen, J.; Yuan, W.; Wu, L.; Tang, Q.; Xia, Q.; Ji, J.; Liu, Z.; Ma, Z.; Zhou, Z.; Cheng, Y.; Shu, X. PDGF-D promotes cell growth, aggressiveness, angiogenesis and EMT transformation of colorectal cancer by activation of Notch1/Twist1 pathway. Oncotarget, 2017, 8(6), 9961-9973.
[http://dx.doi.org/10.18632/oncotarget.14283] [PMID: 28035069]
[11]
Sheng, W.; Chen, C.; Dong, M.; Wang, G.; Zhou, J.; Song, H.; Li, Y.; Zhang, J.; Ding, S. Calreticulin promotes EGF-induced EMT in pancreatic cancer cells via Integrin/EGFR-ERK/MAPK signaling pathway. Cell Death Dis., 2017, 8(10)e3147
[http://dx.doi.org/10.1038/cddis.2017.547] [PMID: 29072694]
[12]
Valiathan, R.R.; Marco, M.; Leitinger, B.; Kleer, C.G.; Fridman, R. Discoidin domain receptor tyrosine kinases: new players in cancer progression. Cancer Metastasis Rev., 2012, 31(1-2), 295-321.
[http://dx.doi.org/10.1007/s10555-012-9346-z] [PMID: 22366781]
[13]
Borza, C.M.; Pozzi, A. Discoidin domain receptors in disease. Matrix Biol., 2014, 34, 185-192.
[http://dx.doi.org/10.1016/j.matbio.2013.12.002] [PMID: 24361528]
[14]
Badaoui, M.; Mimsy-Julienne, C.; Saby, C.; Van Gulick, L.; Peretti, M.; Jeannesson, P.; Morjani, H.; Ouadid-Ahidouch, H. Collagen type 1 promotes survival of human breast cancer cells by overexpressing Kv10.1 potassium and Orai1 calcium channels through DDR1-dependent pathway. Oncotarget, 2017, 9(37), 24653-24671.
[PMID: 29872495]
[15]
Heinzelmann-Schwarz, V.A.; Gardiner-Garden, M.; Henshall, S.M.; Scurry, J.; Scolyer, R.A.; Davies, M.J.; Heinzelmann, M.; Kalish, L.H.; Bali, A.; Kench, J.G.; Edwards, L.S.; Vanden Bergh, P.M.; Hacker, N.F.; Sutherland, R.L.; O’Brien, P.M. Overexpression of the cell adhesion molecules DDR1, Claudin 3, and Ep-CAM in metaplastic ovarian epithelium and ovarian cancer. Clin. Cancer Res., 2004, 10(13), 4427-4436.
[http://dx.doi.org/10.1158/1078-0432.CCR-04-0073] [PMID: 15240533]
[16]
Miao, L.; Zhu, S.; Wang, Y.; Li, Y.; Ding, J.; Dai, J.; Cai, H.; Zhang, D.; Song, Y. Discoidin domain receptor 1 is associated with poor prognosis of non-small cell lung cancer and promotes cell invasion via epithelial-to-mesenchymal transition. Med. Oncol., 2013, 30(3), 626.
[http://dx.doi.org/10.1007/s12032-013-0626-4] [PMID: 23761027]
[17]
Shimada, K.; Nakamura, M.; Ishida, E.; Higuchi, T.; Yamamoto, H.; Tsujikawa, K.; Konishi, N. Prostate cancer antigen-1 contributes to cell survival and invasion though discoidin receptor 1 in human prostate cancer. Cancer Sci., 2008, 99(1), 39-45.
[PMID: 17970783]
[18]
Xie, R.; Wang, X.; Qi, G.; Wu, Z.; Wei, R.; Li, P.; Zhang, D. DDR1 enhances invasion and metastasis of gastric cancer via epithelial-mesenchymal transition. Tumour Biol., 2016, 37(9), 12049-12059.
[http://dx.doi.org/10.1007/s13277-016-5070-6] [PMID: 27179963]
[19]
Suh, Y.S.; Joung, J.Y.; Kim, S.H.; Seo, H.K.; Chung, J.; Lee, K.H. Establishment and application of prostate cancer circulating tumor cells in the Era of precision medicine. BioMed Res. Int., 2017, 2017
[http://dx.doi.org/10.1155/2017/7206307]
[20]
Sethi, S.; Macoska, J.; Chen, W.; Sarkar, F.H. Molecular signature of epithelial-mesenchymal transition (EMT) in human prostate cancer bone metastasis. Am. J. Transl. Res., 2010, 3(1), 90-99.
[PMID: 21139809]
[21]
Azizi, R.; Salemi, Z.; Fallahian, F.; Aghaei, M. Inhibition of didscoidin domain receptor 1 reduces epithelial-mesenchymal transition and induce cell-cycle arrest and apoptosis in prostate cancer cell lines. J. Cell. Physiol., 2019, 234(11), 19539-19552.
[http://dx.doi.org/10.1002/jcp.28552] [PMID: 30963567]
[22]
Wilson, T.R.; Fridlyand, J.; Yan, Y.; Penuel, E.; Burton, L.; Chan, E.; Peng, J.; Lin, E.; Wang, Y.; Sosman, J.; Ribas, A.; Li, J.; Moffat, J.; Sutherlin, D.P.; Koeppen, H.; Merchant, M.; Neve, R.; Settleman, J. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature, 2012, 487(7408), 505-509.
[http://dx.doi.org/10.1038/nature11249] [PMID: 22763448]
[23]
Landesman-Milo, D.; Goldsmith, M.; Leviatan Ben-Arye, S.; Witenberg, B.; Brown, E.; Leibovitch, S.; Azriel, S.; Tabak, S.; Morad, V.; Peer, D. Hyaluronan grafted lipid-based nanoparticles as RNAi carriers for cancer cells. Cancer Lett., 2013, 334(2), 221-227.
[http://dx.doi.org/10.1016/j.canlet.2012.08.024] [PMID: 22935680]
[24]
Betáková, T.; Svančarová, P. Role and application of RNA interference in replication of influenza viruses. Acta Virol., 2013, 57(2), 97-104.
[http://dx.doi.org/10.4149/av_2013_02_97] [PMID: 23600867]
[25]
Zhang, L.; Cheng, F.; He, R.; Chen, H.; Liu, Y.; Sun, J. Inhibition of SATB1 by shRNA suppresses the proliferation of cutaneous malignant melanoma. Cancer Biother. Radiopharm., 2014, 29(2), 77-82.
[http://dx.doi.org/10.1089/cbr.2013.1502] [PMID: 24392879]
[26]
Radisky, D.C. Epithelial-mesenchymal transition. J. Cell Sci., 2005, 118(Pt 19), 4325-4326.
[http://dx.doi.org/10.1242/jcs.02552] [PMID: 16179603]
[27]
Bitting, R.L.; Schaeffer, D.; Somarelli, J.A.; Garcia-Blanco, M.A.; Armstrong, A.J. The role of epithelial plasticity in prostate cancer dissemination and treatment resistance. Cancer Metastasis Rev., 2014, 33(2-3), 441-468.
[http://dx.doi.org/10.1007/s10555-013-9483-z] [PMID: 24414193]
[28]
Xie, X.; Rui, W.; He, W.; Shao, Y.; Sun, F.; Zhou, W.; Wu, Y.; Zhu, Y. Discoidin domain receptor 1 activity drives an aggressive phenotype in bladder cancer. Am. J. Transl. Res., 2017, 9(5), 2500-2507.
[PMID: 28560000]
[29]
Yang, J.C.; Zhang, Y.; He, S.J.; Li, M.M.; Cai, X.L.; Wang, H.; Xu, L.M.; Cao, J. TM4SF1 promotes metastasis of pancreatic cancer via regulating the expression of DDR1. Sci. Rep., 2017, 7, 45895.
[http://dx.doi.org/10.1038/srep45895] [PMID: 28368050]
[30]
Rudra-Ganguly, N.; Lowe, C.; Mattie, M.; Chang, M.S.; Satpayev, D.; Verlinsky, A.; An, Z.; Hu, L.; Yang, P.; Challita-Eid, P.; Stover, D.R.; Pereira, D.S. Discoidin domain receptor 1 contributes to tumorigenesis through modulation of TGFBI expression. PLoS One, 2014, 9(11)e111515
[http://dx.doi.org/10.1371/journal.pone.0111515] [PMID: 25369402]
[31]
Gao, M.; Duan, L.; Luo, J.; Zhang, L.; Lu, X.; Zhang, Y.; Zhang, Z.; Tu, Z.; Xu, Y.; Ren, X.; Ding, K. Discovery and optimization of 3-(2-(Pyrazolo[1,5-a]pyrimidin-6-yl)ethynyl)benzamides as novel selective and orally bioavailable discoidin domain receptor 1 (DDR1) inhibitors. J. Med. Chem., 2013, 56(8), 3281-3295.
[http://dx.doi.org/10.1021/jm301824k] [PMID: 23521020]
[32]
Song, J.; Chen, X.; Bai, J.; Liu, Q.; Li, H.; Xie, J.; Jing, H.; Zheng, J. Discoidin domain receptor 1 (DDR1), a promising biomarker, induces epithelial to mesenchymal transition in renal cancer cells. Tumour Biol., 2016, 37(8), 11509-11521.
[http://dx.doi.org/10.1007/s13277-016-5021-2] [PMID: 27020590]
[33]
Koh, M.; Woo, Y.; Valiathan, R.R.; Jung, H.Y.; Park, S.Y.; Kim, Y.N.; Kim, H.R.C.; Fridman, R.; Moon, A. Discoidin domain receptor 1 is a novel transcriptional target of ZEB1 in breast epithelial cells undergoing H-Ras-induced epithelial to mesenchymal transition. Int. J. Cancer, 2015, 136(6), E508-E520.
[http://dx.doi.org/10.1002/ijc.29154] [PMID: 25155634]
[34]
Wang, C-Z.; Su, H-W.; Hsu, Y-C.; Shen, M-R.; Tang, M-J. A discoidin domain receptor 1/SHP-2 signaling complex inhibits α2β1-integrin-mediated signal transducers and activators of transcription 1/3 activation and cell migration. Mol. Biol. Cell, 2006, 17(6), 2839-2852.
[http://dx.doi.org/10.1091/mbc.e05-11-1068] [PMID: 16611743]
[35]
Yuge, R.; Kitadai, Y.; Takigawa, H.; Naito, T.; Oue, N.; Yasui, W.; Tanaka, S.; Chayama, K. Silencing of Discoidin Domain Receptor-1 (DDR1) concurrently inhibits multiple steps of metastasis cascade in gastric cancer. Transl. Oncol., 2018, 11(3), 575-584.
[http://dx.doi.org/10.1016/j.tranon.2018.02.003] [PMID: 29547756]
[36]
Wu, A.; Chen, Y.; Liu, Y.; Lai, Y.; Liu, D. miR-199b-5p inhibits triple negative breast cancer cell proliferation, migration and invasion by targeting DDR1. Oncol. Lett., 2018, 16(4), 4889-4896.
[http://dx.doi.org/10.3892/ol.2018.9255] [PMID: 30250555]
[37]
Hou, G.; Vogel, W.; Bendeck, M.P. The discoidin domain receptor tyrosine kinase DDR1 in arterial wound repair. J. Clin. Invest., 2001, 107(6), 727-735.
[http://dx.doi.org/10.1172/JCI10720] [PMID: 11254672]
[38]
Wang, Z.; Sun, X.; Bao, Y.; Mo, J.; Du, H.; Hu, J.; Zhang, X. E2F1 silencing inhibits migration and invasion of osteosarcoma cells via regulating DDR1 expression. Int. J. Oncol., 2017, 51(6), 1639-1650.
[http://dx.doi.org/10.3892/ijo.2017.4165] [PMID: 29039472]
[39]
Shintani, Y.; Fukumoto, Y.; Chaika, N.; Svoboda, R.; Wheelock, M.J.; Johnson, K.R. Collagen I-mediated up-regulation of N-cadherin requires cooperative signals from integrins and discoidin domain receptor 1. J. Cell Biol., 2008, 180(6), 1277-1289.
[http://dx.doi.org/10.1083/jcb.200708137] [PMID: 18362184]
[40]
Picascia, A.; Stanzione, R.; Chieffi, P.; Kisslinger, A.; Dikic, I.; Tramontano, D. Proline-rich tyrosine kinase 2 regulates proliferation and differentiation of prostate cells. Mol. Cell. Endocrinol., 2002, 186(1), 81-87.
[http://dx.doi.org/10.1016/S0303-7207(01)00667-0] [PMID: 11850124]
[41]
Cao, J.; Liu, J.; Long, J.; Fu, J.; Huang, L.; Li, J.; Liu, C.; Zhang, X.; Yan, Y. microRNA-23b suppresses epithelial-mesenchymal transition (EMT) and metastasis in hepatocellular carcinoma via targeting Pyk2. Biomed. Pharmacother., 2017, 89, 642-650.
[http://dx.doi.org/10.1016/j.biopha.2017.02.030] [PMID: 28262617]
[42]
Kyriakis, J.M.; Avruch, J. Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update. Physiol. Rev., 2012, 92(2), 689-737.
[http://dx.doi.org/10.1152/physrev.00028.2011] [PMID: 22535895]
[43]
Lotan, T.L.; Lyon, M.; Huo, D.; Taxy, J.B.; Brendler, C.; Foster, B.A.; Stadler, W.; Rinker-Schaeffer, C.W. Up-regulation of MKK4, MKK6 and MKK7 during prostate cancer progression: an important role for SAPK signalling in prostatic neoplasia. J. Pathol. J. Patholog. Soc. Great Brit. Ireland, 2007, 212(4), 386-394.
[44]
Assent, D.; Bourgot, I.; Hennuy, B.; Geurts, P.; Noël, A.; Foidart, J-M.; Maquoi, E. A membrane-type-1 matrix metalloproteinase (MT1-MMP)-discoidin domain receptor 1 axis regulates collagen-induced apoptosis in breast cancer cells. PLoS One, 2015, 10(3)e0116006
[http://dx.doi.org/10.1371/journal.pone.0116006] [PMID: 25774665]

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