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Current Molecular Pharmacology

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ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

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Research Article

PF-04449913 Inhibits Proliferation and Metastasis of Colorectal Cancer Cells by Down-regulating MMP9 Expression through the ERK/p65 Pathway

Author(s): Yejiao Ruan, Guangrong Lu, Yaojun Yu, Yue Luo, Hao Wu, Yating Shen, Zejun Gao, Yao Shen, Zhenzhai Cai* and Liyi Li*

Volume 17, 2024

Published on: 13 October, 2023

Article ID: e150923221164 Pages: 13

DOI: 10.2174/1874467217666230915125622

open_access

Abstract

Introduction: Colorectal cancer remains a life-threatening malignancy with increasing morbidity and mortality worldwide. Therefore, new and effective anticolorectal cancer therapeutics are urgently needed.

Methods: In this study, we have studied the anti-tumor properties and potential mechanisms of PF-04449913. Colorectal cancer cell viability was reduced by PF-04449913 in a dose-dependent manner. The migration and invasion ability of malignant colon cells were attenuated by the drug, as demonstrated by the Transwell test. Moreover, PF-04449913 repressed the phosphorylation levels of ERK and other proteins, and the expression levels of MMP9. The anti-tumor effects of the drug in vivo were demonstrated in BALB/c-nude mice models, and PF-04449913 inhibited the malignant phenotype of colorectal cancer cells, including reduction of tumor size and promotion of apoptosis. At the molecular level, PF-04449913 induced a significant decrease in ERK and p65 protein phosphorylation levels and inhibited MMP9 protein expression.

Results: Both in vivo and in vitro results showed PF-04449913 to demonstrate antitumor effects, which have been proposed to be mediated through blockade of the ERK/p65 signaling pathway, and subsequent repression of MMP9 expression.

Conclusion: Our study provides a new perspective on the potential clinical application of PF-04449913 in the treatment of colorectal cancer.

Keywords: PF-04449913, Proliferation, Metastasis, Colorectal cancer, MMP9 expression, ERK/p65 pathway.

[1]
Benson, A.B.; Venook, A.P.; Al-Hawary, M.M.; Arain, M.A.; Chen, Y.J.; Ciombor, K.K.; Cohen, S.; Cooper, H.S.; Deming, D.; Farkas, L.; Garrido-Laguna, I.; Grem, J.L.; Gunn, A.; Hecht, J.R.; Hoffe, S.; Hubbard, J.; Hunt, S.; Johung, K.L.; Kirilcuk, N.; Krishnamurthi, S.; Messersmith, W.A.; Meyerhardt, J.; Miller, E.D.; Mulcahy, M.F.; Nurkin, S.; Overman, M.J.; Parikh, A.; Patel, H.; Pedersen, K.; Saltz, L.; Schneider, C.; Shibata, D.; Skibber, J.M.; Sofocleous, C.T.; Stoffel, E.M.; Stotsky-Himelfarb, E.; Willett, C.G.; Gregory, K.M.; Gurski, L.A. Colon cancer, version 2.2021, NCCN clinical practice guidelines in oncology. J. Natl. Compr. Canc. Netw., 2021, 19(3), 329-359.
[http://dx.doi.org/10.6004/jnccn.2021.0012] [PMID: 33724754]
[2]
Cheng, Y.C.; Wu, P.H.; Chen, Y.J.; Yang, C.H.; Huang, J.L.; Chou, Y.C.; Chang, P.K.; Wen, C.C.; Jao, S.W.; Huang, H.H.; Tsai, Y.H.; Pai, T.W. Using comorbidity pattern analysis to detect reliable methylated genes in colorectal cancer verified by stool DNA test. Genes., 2021, 12(10), 1539.
[http://dx.doi.org/10.3390/genes12101539] [PMID: 34680934]
[3]
Martinelli, E.; Martini, G.; Troiani, T. Oxaliplatin plus fluoropyrimidines as adjuvant therapy for colon cancer in older patients: A subgroup analysis from the TOSCA trial. Eur. J. Cancer, 2020, 31, S409-S410.
[http://dx.doi.org/10.1016/j.ejca.2021.01.051]
[4]
Ma, L.; Young, J.; Prabhala, H.; Pan, E.; Mestdagh, P.; Muth, D.; Teruya-Feldstein, J.; Reinhardt, F.; Onder, T.T.; Valastyan, S.; Westermann, F.; Speleman, F.; Vandesompele, J.; Weinberg, R.A. miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis. Nat. Cell Biol., 2010, 12(3), 247-256.
[http://dx.doi.org/10.1038/ncb2024] [PMID: 20173740]
[5]
Wolska-Washer, A.; Robak, T. Glasdegib in the treatment of acute myeloid leukemia. Future. Oncol., 2019, 15(28), 3219-3232.
[http://dx.doi.org/10.2217/fon-2019-0171] [PMID: 31432695]
[6]
Sallman, D.A.; Komrokji, R.S.; Sweet, K.L.; Mo, Q.; McGraw, K.L.; Duong, V.H.; Zhang, L.; Nardelli, L.A.; Padron, E.; List, A.F.; Lancet, J.E. A phase 2 trial of the oral smoothened inhibitor glasdegib in refractory myelodysplastic syndromes (MDS). Leuk. Res., 2019, 81, 56-61.
[http://dx.doi.org/10.1016/j.leukres.2019.03.008] [PMID: 31030089]
[7]
Goldsmith, S.R.; Lovell, A.R.; Schroeder, M.A. Glasdegib for the treatment of adult patients with newly diagnosed acute myeloid leukemia or high-grade myelodysplastic syndrome who are elderly or otherwise unfit for standard induction chemotherapy. Drugs. Today., 2019, 55(9), 545-562.
[http://dx.doi.org/10.1358/dot.2019.55.9.3020160] [PMID: 31584572]
[8]
Katoh, M. Genomic testing, tumor microenvironment and targeted therapy of Hedgehog-related human cancers. Clin. Sci., 2019, 133(8), 953-970.
[http://dx.doi.org/10.1042/CS20180845] [PMID: 31036756]
[9]
Bonilla, X.; Parmentier, L.; King, B.; Bezrukov, F.; Kaya, G.; Zoete, V.; Seplyarskiy, V.B.; Sharpe, H.J.; McKee, T.; Letourneau, A.; Ribaux, P.G.; Popadin, K.; Basset-Seguin, N.; Chaabene, R.B.; Santoni, F.A.; Andrianova, M.A.; Guipponi, M.; Garieri, M.; Verdan, C.; Grosdemange, K.; Sumara, O.; Eilers, M.; Aifantis, I.; Michielin, O.; de Sauvage, F.J.; Antonarakis, S.E.; Nikolaev, S.I. Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma. Nat. Genet., 2016, 48(4), 398-406.
[http://dx.doi.org/10.1038/ng.3525] [PMID: 26950094]
[10]
Kool, M.; Jones, D.T.W.; Jäger, N.; Northcott, P.A.; Pugh, T.J.; Hovestadt, V.; Piro, R.M.; Esparza, L.A.; Markant, S.L.; Remke, M.; Milde, T.; Bourdeaut, F.; Ryzhova, M.; Sturm, D.; Pfaff, E.; Stark, S.; Hutter, S.; Şeker-Cin, H.; Johann, P.; Bender, S.; Schmidt, C.; Rausch, T.; Shih, D.; Reimand, J.; Sieber, L.; Wittmann, A.; Linke, L.; Witt, H.; Weber, U.D.; Zapatka, M.; König, R.; Beroukhim, R.; Bergthold, G.; van Sluis, P.; Volckmann, R.; Koster, J.; Versteeg, R.; Schmidt, S.; Wolf, S.; Lawerenz, C.; Bartholomae, C.C.; von Kalle, C.; Unterberg, A.; Herold-Mende, C.; Hofer, S.; Kulozik, A.E.; von Deimling, A.; Scheurlen, W.; Felsberg, J.; Reifenberger, G.; Hasselblatt, M.; Crawford, J.R.; Grant, G.A.; Jabado, N.; Perry, A.; Cowdrey, C.; Croul, S.; Zadeh, G.; Korbel, J.O.; Doz, F.; Delattre, O.; Bader, G.D.; McCabe, M.G.; Collins, V.P.; Kieran, M.W.; Cho, Y.J.; Pomeroy, S.L.; Witt, O.; Brors, B.; Taylor, M.D.; Schüller, U.; Korshunov, A.; Eils, R.; Wechsler-Reya, R.J.; Lichter, P.; Pfister, S.M. Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer. Cell., 2014, 25(3), 393-405.
[http://dx.doi.org/10.1016/j.ccr.2014.02.004] [PMID: 24651015]
[11]
Hainsworth, J.D. Targeted therapy for advanced solid tumorson the basis of molecular profiles Results from MyPathway. J. Clin. Oncol., 2018, 36(6), 536-542.
[http://dx.doi.org/10.1200/JCO.2017.75.3780] [PMID: 29320312]
[12]
Witkiewicz, A.K.; McMillan, E.A.; Balaji, U.; Baek, G.; Lin, W.C.; Mansour, J.; Mollaee, M.; Wagner, K.U.; Koduru, P.; Yopp, A.; Choti, M.A.; Yeo, C.J.; McCue, P.; White, M.A.; Knudsen, E.S. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat. Commun., 2015, 6(1), 6744.
[http://dx.doi.org/10.1038/ncomms7744] [PMID: 25855536]
[13]
Brastianos, P.K.; Horowitz, P.M.; Santagata, S.; Jones, R.T.; McKenna, A.; Getz, G.; Ligon, K.L.; Palescandolo, E.; Van Hummelen, P.; Ducar, M.D.; Raza, A.; Sunkavalli, A.; MacConaill, L.E.; Stemmer-Rachamimov, A.O.; Louis, D.N.; Hahn, W.C.; Dunn, I.F.; Beroukhim, R. Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations. Nat. Genet., 2013, 45(3), 285-289.
[http://dx.doi.org/10.1038/ng.2526] [PMID: 23334667]
[14]
Lee, J.J.; Chu, E. Sequencing of antiangiogenic agents in the treatment of metastatic colorectal cancer. Clin. Colorectal. Cancer., 2014, 13(3), 135-144.
[http://dx.doi.org/10.1016/j.clcc.2014.02.001] [PMID: 24768040]
[15]
Brechbiel, J.; Miller-Moslin, K.; Adjei, A.A. Crosstalk between hedgehog and other signaling pathways as a basis for combination therapies in cancer. Cancer Treat. Rev., 2014, 40(6), 750-759.
[http://dx.doi.org/10.1016/j.ctrv.2014.02.003] [PMID: 24613036]
[16]
Xu, H.; Dun, S.; Gao, Y.; Ming, J.; Hui, L.; Qiu, X. TMEM107 inhibits EMT and invasion of NSCLC through regulating the H edgehog pathway. Thorac. Cancer., 2021, 12(1), 79-89.
[http://dx.doi.org/10.1111/1759-7714.13715] [PMID: 33124203]
[17]
Du, F.Y.; Zhou, Q.F.; Sun, W.J.; Chen, G.L. Targeting cancer stem cells in drug discovery: Current state and future perspectives. World J. Stem Cells, 2019, 11(7), 398-420.
[http://dx.doi.org/10.4252/wjsc.v11.i7.398] [PMID: 31396368]
[18]
Fukushima, N.; Minami, Y.; Kakiuchi, S.; Kuwatsuka, Y.; Hayakawa, F.; Jamieson, C.; Kiyoi, H.; Naoe, T. Small‐molecule Hedgehog inhibitor attenuates the leukemia‐initiation potential of acute myeloid leukemia cells. Cancer Sci., 2016, 107(10), 1422-1429.
[http://dx.doi.org/10.1111/cas.13019] [PMID: 27461445]
[19]
Lauressergues, E.; Heusler, P.; Lestienne, F.; Troulier, D.; Rauly-Lestienne, I.; Tourette, A.; Ailhaud, M.C.; Cathala, C.; Tardif, S.; Denais-Laliève, D.; Calmettes, M.T.; Degryse, A.D.; Dumoulin, A.; De Vries, L.; Cussac, D. Pharmacological evaluation of a series of smoothened antagonists in signaling pathways and after topical application in a depilated mouse model. Pharmacol. Res. Perspect., 2016, 4(2), e00214.
[http://dx.doi.org/10.1002/prp2.214] [PMID: 27069629]
[20]
Taipale, J.; Beachy, P.A. The Hedgehog and Wnt signalling pathways in cancer. Nature., 2001, 411(6835), 349-354.
[http://dx.doi.org/10.1038/35077219] [PMID: 11357142]
[21]
Konstantinou, D.; Bertaux-Skeirik, N.; Zavros, Y. Hedgehog signaling in the stomach. Curr. Opin. Pharmacol., 2016, 31, 76-82.
[http://dx.doi.org/10.1016/j.coph.2016.09.003] [PMID: 27750091]
[22]
Haveri, H.; Westerholm-Ormio, M.; Lindfors, K.; Mäki, M.; Savilahti, E.; Andersson, L.C.; Heikinheimo, M. Transcription factors GATA-4 and GATA-6 in normal and neoplastic human gastrointestinal mucosa. BMC Gastroenterol., 2008, 8(1), 9.
[http://dx.doi.org/10.1186/1471-230X-8-9] [PMID: 18405344]
[23]
Varnat, F.; Duquet, A.; Malerba, M.; Zbinden, M.; Mas, C.; Gervaz, P.; Ruiz i Altaba, A. Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion. EMBO Mol. Med., 2009, 1(6-7), 338-351.
[http://dx.doi.org/10.1002/emmm.200900039] [PMID: 20049737]
[24]
Wang, W.; Li, Q.; Yang, Z.; Duan, L.; Yu, K.; Zhang, L.; Li, Y.; Cai, X.; Shen, T.; Xiong, W. Synergistic inhibition of colon carcinoma cell growth by Hedgehog-Gli1 inhibitor arsenic trioxide and phosphoinositide 3-kinase inhibitor LY294002. OncoTargets Ther., 2015, 8, 877-883.
[http://dx.doi.org/10.2147/OTT.S71034] [PMID: 25945059]
[25]
Mazumdar, T.; DeVecchio, J.; Agyeman, A.; Shi, T.; Houghton, J.A. The GLI genes as the molecular switch in disrupting Hedgehog signaling in colon cancer. Oncotarget, 2011, 2(8), 638-645.
[http://dx.doi.org/10.18632/oncotarget.310] [PMID: 21860067]
[26]
Huanxian, W.; Lishun, Z.; Boyu, C.; Baofang, O.; Jiahuan, X.; Nannan, T.; Danni, D.; Yangcheng, A.; Qianqing, C.; Dongling, Q.; Tingting, Z.; Lin, L.; Yuanxin, T.; Jiajie, Z.; Shaoyu, W. B13, a well-tolerated inhibitor of hedgehog pathway, exhibited potent anti-tumor effects against colorectal carcinoma in vitro and in vivo. Bioorg. Chem., 2011, 135, 106488.
[27]
Seto, M.; Ohta, M.; Asaoka, Y.; Ikenoue, T.; Tada, M.; Miyabayashi, K.; Mohri, D.; Tanaka, Y.; Ijichi, H.; Tateishi, K.; Kanai, F.; Kawabe, T.; Omata, M. Regulation of the hedgehog signaling by the mitogen-activated protein kinase cascade in gastric cancer. Mol. Carcinog., 2009, 48(8), 703-712.
[http://dx.doi.org/10.1002/mc.20516] [PMID: 19142899]
[28]
Chen, J.; Stark, L. Aspirin prevention of colorectal cancer: Focus on NF-κB signalling and the nucleolus. Biomedicines., 2017, 5(3), 43.
[http://dx.doi.org/10.3390/biomedicines5030043] [PMID: 28718829]
[29]
Zhang, H.; Xie, L.; Zhang, N.; Qi, X.; Lu, T.; Xing, J.; Akhtar, M.F.; Li, L.; Liu, G. Donkey Oil-based ketogenic diet prevents tumor progression by regulating intratumor inflammation, metastasis and angiogenesis in CT26 tumor-bearing mice. Genes., 2023, 14(5), 1024.
[http://dx.doi.org/10.3390/genes14051024] [PMID: 37239383]
[30]
Li, S.; Ung, T.T.; Nguyen, T.T.; Sah, D.K.; Park, S.Y.; Jung, Y.D. Cholic acid stimulates MMP-9 in human colon cancer cells via activation of MAPK, AP-1, and NF-κB activity. Int. J. Mol. Sci., 2020, 21(10), 3420.
[http://dx.doi.org/10.3390/ijms21103420] [PMID: 32408577]
[31]
Buhrmann, C.; Kunnumakkara, A.; Popper, B.; Majeed, M.; Aggarwal, B.; Shakibaei, M. Calebin a potentiates the effect of 5-FU and TNF-β (Lymphotoxin α) against human colorectal cancer cells: Potential role of NF-κB. Int. J. Mol. Sci., 2020, 21(7), 2393.
[http://dx.doi.org/10.3390/ijms21072393] [PMID: 32244288]
[32]
Yang, M.; Li, W.Y.; Xie, J.; Wang, Z.L.; Wen, Y.L.; Zhao, C.C.; Tao, L.; Li, L.F.; Tian, Y.; Sheng, J. Astragalin inhibits the proliferation and migration of human colon cancer HCT116 cells by regulating the NF-κB signaling pathway. Front. Pharmacol., 2021, 12, 639256.
[http://dx.doi.org/10.3389/fphar.2021.639256] [PMID: 33953676]
[33]
Owczarek, K.; Hrabec, E.; Fichna, J.; Sosnowska, D.; Koziołkiewicz, M.; Szymański, J.; Lewandowska, U. Flavanols from Japanese quince (Chaenomeles japonica) fruit suppress expression of cyclooxygenase-2, metalloproteinase-9, and nuclear factor-kappaB in human colon cancer cells. Acta Biochim. Pol., 2017, 64(3), 567-576.
[http://dx.doi.org/10.18388/abp.2017_1599] [PMID: 28787469]
[34]
Yu, Y.; Wang, J.L.; Meng, L.L.; Hu, C.T.; Yan, Z.W.; He, Z.P.; Shi, X.Q.; Fu, G.H.; Zu, L.D. DDX54 plays a cancerous role through activating P65 and AKT signaling pathway in colorectal cancer. Front. Oncol., 2021, 11, 650360.
[http://dx.doi.org/10.3389/fonc.2021.650360] [PMID: 33968751]
[35]
Li, X.; Wang, N.; Wu, Y.; Liu, Y.; Wang, R. ALDH6A1 weakens the progression of colon cancer via modulating the RAS/RAF/MEK/ERK pathway in cancer cell lines. Gene., 2022, 842, 146757.
[http://dx.doi.org/10.1016/j.gene.2022.146757] [PMID: 35907565]
[36]
Yang, X.; Zheng, Y.; Rong, W. Sevoflurane induces apoptosis and inhibits the growth and motility of colon cancer in vitro and in vivovia inactivating Ras/Raf/MEK/ERK signaling. Life Sci., 2019, 239, 116916.
[http://dx.doi.org/10.1016/j.lfs.2019.116916] [PMID: 31626792]
[37]
Romayor, I.; Badiola, I.; Olaso, E. Inhibition of DDR1 reduces invasive features of human A375 melanoma, HT29 colon carcinoma and SK-HEP hepatoma cells. Cell Adhes. Migr., 2020, 14(1), 69-81.
[http://dx.doi.org/10.1080/19336918.2020.1733892] [PMID: 32090682]
[38]
Li, X.; Bao, C.; Ma, Z.; Xu, B.; Ying, X.; Liu, X.; Zhang, X. Perfluorooctanoic acid stimulates ovarian cancer cell migration, invasion via ERK/NF-κB/MMP-2/-9 pathway. Toxicol. Lett., 2018, 294, 44-50.
[http://dx.doi.org/10.1016/j.toxlet.2018.05.009] [PMID: 29753068]
[39]
Ha, S.H.; Kwon, K.M.; Park, J.Y.; Abekura, F.; Lee, Y.C.; Chung, T.W.; Ha, K.T.; Chang, H.W.; Cho, S.H.; Kim, J.S.; Kim, C.H. Esculentoside H inhibits colon cancer cell migration and growth through suppression of MMP-9 gene expression via NF‐kB signaling pathway. J. Cell. Biochem., 2019, 120(6), 9810-9819.
[http://dx.doi.org/10.1002/jcb.28261] [PMID: 30525244]
[40]
Zhang, W.; Wang, F.; Xu, P.; Miao, C.; Zeng, X.; Cui, X.; Lu, C.; Xie, H.; Yin, H.; Chen, F.; Ma, J.; Gao, S.; Fu, Z. Perfluorooctanoic acid stimulates breast cancer cells invasion and up-regulates matrix metalloproteinase-2/-9 expression mediated by activating NF-κB. Toxicol. Lett., 2014, 229(1), 118-125.
[http://dx.doi.org/10.1016/j.toxlet.2014.06.004] [PMID: 24960061]
[41]
Jiang, H.; Zhou, Z.; Jin, S.; Xu, K.; Zhang, H.; Xu, J.; Sun, Q.; Wang, J.; Xu, J. PRMT 9 promotes hepatocellular carcinoma invasion and metastasis via activating PI 3K/Akt/ GSK ‐3β/Snail signaling. Cancer Sci., 2018, 109(5), 1414-1427.
[http://dx.doi.org/10.1111/cas.13598] [PMID: 29603830]
[42]
Idiiatullina, E.; Al-Azab, M.; Walana, W.; Pavlov, V.; Liu, B. EnDuo, a novel derivative of Endostar, inhibits the migration of colon cancer cells, suppresses matrix metalloproteinase-2/9 expression and impedes AKT/ERK activation. Biomed. Pharmacother., 2021, 134, 111136.
[http://dx.doi.org/10.1016/j.biopha.2020.111136] [PMID: 33341042]
[43]
Esfahanian, N.; Shakiba, Y.; Nikbin, B.; Soraya, H.; Maleki-Dizaji, N.; Ghazi-Khansari, M.; Garjani, A. Effect of metformin on the proliferation, migration, and MMP-2 and -9 expression of human umbilical vein endothelial cells. Mol. Med. Rep., 2012, 5(4), 1068-1074.
[http://dx.doi.org/10.3892/mmr.2012.753] [PMID: 22246099]
[44]
Serala, K.; Steenkamp, P.; Mampuru, L.; Prince, S.; Poopedi, K.; Mbazima, V. in vitro antimetastatic activity ofMOMORDICA BALSAMINA crude acetone extract in HT -29 human colon cancer cells. Environ. Toxicol., 2021, 36(11), 2196-2205.
[http://dx.doi.org/10.1002/tox.23333] [PMID: 34272816]

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