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Volume 17, Issue 1
  • ISSN: 1874-4672
  • E-ISSN: 1874-4702
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Abstract

Introduction

Colorectal cancer remains a life-threatening malignancy with increasing morbidity and mortality worldwide. Therefore, new and effective anti-colorectal 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 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 and 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.

© 2024 The Author(s). Published by Bentham Science Publisher.
This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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2024-01-01
2024-11-26

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References

  1. BensonA.B. VenookA.P. Al-HawaryM.M. ArainM.A. ChenY.J. CiomborK.K. CohenS. CooperH.S. DemingD. FarkasL. Garrido-LagunaI. GremJ.L. GunnA. HechtJ.R. HoffeS. HubbardJ. HuntS. JohungK.L. KirilcukN. KrishnamurthiS. MessersmithW.A. MeyerhardtJ. MillerE.D. MulcahyM.F. NurkinS. OvermanM.J. ParikhA. PatelH. PedersenK. SaltzL. SchneiderC. ShibataD. SkibberJ.M. SofocleousC.T. StoffelE.M. Stotsky-HimelfarbE. WillettC.G. GregoryK.M. GurskiL.A. Colon cancer, version 2.2021, NCCN clinical practice guidelines in oncology.J. Natl. Compr. Canc. Netw.202119332935910.6004/jnccn.2021.001233724754
     [Google Scholar]
  2. ChengY.C. WuP.H. ChenY.J. YangC.H. HuangJ.L. ChouY.C. ChangP.K. WenC.C. JaoS.W. HuangH.H. TsaiY.H. PaiT.W. Using comorbidity pattern analysis to detect reliable methylated genes in colorectal cancer verified by stool DNA test.Genes.20211210153910.3390/genes1210153934680934
     [Google Scholar]
  3. MartinelliE. MartiniG. TroianiT. Oxaliplatin plus fluoropyrimidines as adjuvant therapy for colon cancer in older patients: A subgroup analysis from the TOSCA trial.Eur. J. Cancer202031S409S41010.1016/j.ejca.2021.01.051
     [Google Scholar]
  4. MaL. YoungJ. PrabhalaH. PanE. MestdaghP. MuthD. Teruya-FeldsteinJ. ReinhardtF. OnderT.T. ValastyanS. WestermannF. SpelemanF. VandesompeleJ. WeinbergR.A. miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis.Nat. Cell Biol.201012324725610.1038/ncb202420173740
     [Google Scholar]
  5. Wolska-WasherA. RobakT. Glasdegib in the treatment of acute myeloid leukemia.Future. Oncol.201915283219323210.2217/fon‑2019‑017131432695
     [Google Scholar]
  6. SallmanD.A. KomrokjiR.S. SweetK.L. MoQ. McGrawK.L. DuongV.H. ZhangL. NardelliL.A. PadronE. ListA.F. LancetJ.E. A phase 2 trial of the oral smoothened inhibitor glasdegib in refractory myelodysplastic syndromes (MDS).Leuk. Res.201981566110.1016/j.leukres.2019.03.00831030089
     [Google Scholar]
  7. GoldsmithS.R. LovellA.R. SchroederM.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.201955954556210.1358/dot.2019.55.9.302016031584572
     [Google Scholar]
  8. KatohM. Genomic testing, tumor microenvironment and targeted therapy of Hedgehog-related human cancers.Clin. Sci.2019133895397010.1042/CS2018084531036756
     [Google Scholar]
  9. BonillaX. ParmentierL. KingB. BezrukovF. KayaG. ZoeteV. SeplyarskiyV.B. SharpeH.J. McKeeT. LetourneauA. RibauxP.G. PopadinK. Basset-SeguinN. ChaabeneR.B. SantoniF.A. AndrianovaM.A. GuipponiM. GarieriM. VerdanC. GrosdemangeK. SumaraO. EilersM. AifantisI. MichielinO. de SauvageF.J. AntonarakisS.E. NikolaevS.I. Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma.Nat. Genet.201648439840610.1038/ng.352526950094
     [Google Scholar]
  10. KoolM. JonesD.T.W. JägerN. NorthcottP.A. PughT.J. HovestadtV. PiroR.M. EsparzaL.A. MarkantS.L. RemkeM. MildeT. BourdeautF. RyzhovaM. SturmD. PfaffE. StarkS. HutterS. Şeker-CinH. JohannP. BenderS. SchmidtC. RauschT. ShihD. ReimandJ. SieberL. WittmannA. LinkeL. WittH. WeberU.D. ZapatkaM. KönigR. BeroukhimR. BergtholdG. van SluisP. VolckmannR. KosterJ. VersteegR. SchmidtS. WolfS. LawerenzC. BartholomaeC.C. von KalleC. UnterbergA. Herold-MendeC. HoferS. KulozikA.E. von DeimlingA. ScheurlenW. FelsbergJ. ReifenbergerG. HasselblattM. CrawfordJ.R. GrantG.A. JabadoN. PerryA. CowdreyC. CroulS. ZadehG. KorbelJ.O. DozF. DelattreO. BaderG.D. McCabeM.G. CollinsV.P. KieranM.W. ChoY.J. PomeroyS.L. WittO. BrorsB. TaylorM.D. SchüllerU. KorshunovA. EilsR. Wechsler-ReyaR.J. LichterP. PfisterS.M. Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition.Cancer. Cell.201425339340510.1016/j.ccr.2014.02.00424651015
     [Google Scholar]
  11. HainsworthJ.D. Targeted therapy for advanced solid tumorson the basis of molecular profiles Results from MyPathway.J. Clin. Oncol.201836653654210.1200/JCO.2017.75.378029320312
     [Google Scholar]
  12. WitkiewiczA.K. McMillanE.A. BalajiU. BaekG. LinW.C. MansourJ. MollaeeM. WagnerK.U. KoduruP. YoppA. ChotiM.A. YeoC.J. McCueP. WhiteM.A. KnudsenE.S. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets.Nat. Commun.201561674410.1038/ncomms774425855536
     [Google Scholar]
  13. BrastianosP.K. HorowitzP.M. SantagataS. JonesR.T. McKennaA. GetzG. LigonK.L. PalescandoloE. Van HummelenP. DucarM.D. RazaA. SunkavalliA. MacConaillL.E. Stemmer-RachamimovA.O. LouisD.N. HahnW.C. DunnI.F. BeroukhimR. Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations.Nat. Genet.201345328528910.1038/ng.252623334667
     [Google Scholar]
  14. LeeJ.J. ChuE. Sequencing of antiangiogenic agents in the treatment of metastatic colorectal cancer.Clin. Colorectal. Cancer.201413313514410.1016/j.clcc.2014.02.00124768040
     [Google Scholar]
  15. BrechbielJ. Miller-MoslinK. AdjeiA.A. Crosstalk between hedgehog and other signaling pathways as a basis for combination therapies in cancer.Cancer Treat. Rev.201440675075910.1016/j.ctrv.2014.02.00324613036
     [Google Scholar]
  16. XuH. DunS. GaoY. MingJ. HuiL. QiuX. TMEM107 inhibits EMT and invasion of NSCLC through regulating the H edgehog pathway.Thorac. Cancer.2021121798910.1111/1759‑7714.1371533124203
     [Google Scholar]
  17. DuF.Y. ZhouQ.F. SunW.J. ChenG.L. Targeting cancer stem cells in drug discovery: Current state and future perspectives.World J. Stem Cells201911739842010.4252/wjsc.v11.i7.39831396368
     [Google Scholar]
  18. FukushimaN. MinamiY. KakiuchiS. KuwatsukaY. HayakawaF. JamiesonC. KiyoiH. NaoeT. Small‐molecule Hedgehog inhibitor attenuates the leukemia‐initiation potential of acute myeloid leukemia cells.Cancer Sci.2016107101422142910.1111/cas.1301927461445
     [Google Scholar]
  19. LauresserguesE. HeuslerP. LestienneF. TroulierD. Rauly-LestienneI. TouretteA. AilhaudM.C. CathalaC. TardifS. Denais-LalièveD. CalmettesM.T. DegryseA.D. DumoulinA. De VriesL. CussacD. Pharmacological evaluation of a series of smoothened antagonists in signaling pathways and after topical application in a depilated mouse model.Pharmacol. Res. Perspect.201642e0021410.1002/prp2.21427069629
     [Google Scholar]
  20. TaipaleJ. BeachyP.A. The Hedgehog and Wnt signalling pathways in cancer.Nature.2001411683534935410.1038/3507721911357142
     [Google Scholar]
  21. KonstantinouD. Bertaux-SkeirikN. ZavrosY. Hedgehog signaling in the stomach.Curr. Opin. Pharmacol.201631768210.1016/j.coph.2016.09.00327750091
     [Google Scholar]
  22. HaveriH. Westerholm-OrmioM. LindforsK. MäkiM. SavilahtiE. AnderssonL.C. HeikinheimoM. Transcription factors GATA-4 and GATA-6 in normal and neoplastic human gastrointestinal mucosa.BMC Gastroenterol.200881910.1186/1471‑230X‑8‑918405344
     [Google Scholar]
  23. VarnatF. DuquetA. MalerbaM. ZbindenM. MasC. GervazP. Ruiz i AltabaA. 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.200916-733835110.1002/emmm.20090003920049737
     [Google Scholar]
  24. WangW. LiQ. YangZ. DuanL. YuK. ZhangL. LiY. CaiX. ShenT. XiongW. Synergistic inhibition of colon carcinoma cell growth by Hedgehog-Gli1 inhibitor arsenic trioxide and phosphoinositide 3-kinase inhibitor LY294002.OncoTargets Ther.2015887788310.2147/OTT.S7103425945059
     [Google Scholar]
  25. MazumdarT. DeVecchioJ. AgyemanA. ShiT. HoughtonJ.A. The GLI genes as the molecular switch in disrupting Hedgehog signaling in colon cancer.Oncotarget20112863864510.18632/oncotarget.31021860067
     [Google Scholar]
  26. HuanxianW. LishunZ. BoyuC. BaofangO. JiahuanX. NannanT. DanniD. YangchengA. QianqingC. DonglingQ. TingtingZ. LinL. YuanxinT. JiajieZ. ShaoyuW. B13, a well-tolerated inhibitor of hedgehog pathway, exhibited potent anti-tumor effects against colorectal carcinoma in vitro and in vivo.Bioorg. Chem.2011135106488
     [Google Scholar]
  27. SetoM. OhtaM. AsaokaY. IkenoueT. TadaM. MiyabayashiK. MohriD. TanakaY. IjichiH. TateishiK. KanaiF. KawabeT. OmataM. Regulation of the hedgehog signaling by the mitogen-activated protein kinase cascade in gastric cancer.Mol. Carcinog.200948870371210.1002/mc.2051619142899
     [Google Scholar]
  28. ChenJ. StarkL. Aspirin prevention of colorectal cancer: Focus on NF-κB signalling and the nucleolus.Biomedicines.2017534310.3390/biomedicines503004328718829
     [Google Scholar]
  29. ZhangH. XieL. ZhangN. QiX. LuT. XingJ. AkhtarM.F. LiL. LiuG. Donkey Oil-based ketogenic diet prevents tumor progression by regulating intratumor inflammation, metastasis and angiogenesis in CT26 tumor-bearing mice.Genes.2023145102410.3390/genes1405102437239383
     [Google Scholar]
  30. LiS. UngT.T. NguyenT.T. SahD.K. ParkS.Y. JungY.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.20202110342010.3390/ijms2110342032408577
     [Google Scholar]
  31. BuhrmannC. KunnumakkaraA. PopperB. MajeedM. AggarwalB. ShakibaeiM. 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.2020217239310.3390/ijms2107239332244288
     [Google Scholar]
  32. YangM. LiW.Y. XieJ. WangZ.L. WenY.L. ZhaoC.C. TaoL. LiL.F. TianY. ShengJ. Astragalin inhibits the proliferation and migration of human colon cancer HCT116 cells by regulating the NF-κB signaling pathway.Front. Pharmacol.20211263925610.3389/fphar.2021.63925633953676
     [Google Scholar]
  33. OwczarekK. HrabecE. FichnaJ. SosnowskaD. KoziołkiewiczM. SzymańskiJ. LewandowskaU. 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.201764356757610.18388/abp.2017_159928787469
     [Google Scholar]
  34. YuY. WangJ.L. MengL.L. HuC.T. YanZ.W. HeZ.P. ShiX.Q. FuG.H. ZuL.D. DDX54 plays a cancerous role through activating P65 and AKT signaling pathway in colorectal cancer.Front. Oncol.20211165036010.3389/fonc.2021.65036033968751
     [Google Scholar]
  35. LiX. WangN. WuY. LiuY. WangR. ALDH6A1 weakens the progression of colon cancer via modulating the RAS/RAF/MEK/ERK pathway in cancer cell lines.Gene.202284214675710.1016/j.gene.2022.14675735907565
     [Google Scholar]
  36. YangX. ZhengY. RongW. Sevoflurane induces apoptosis and inhibits the growth and motility of colon cancer in vitro and in vivo via inactivating Ras/Raf/MEK/ERK signaling.Life Sci.201923911691610.1016/j.lfs.2019.11691631626792
     [Google Scholar]
  37. RomayorI. BadiolaI. OlasoE. Inhibition of DDR1 reduces invasive features of human A375 melanoma, HT29 colon carcinoma and SK-HEP hepatoma cells.Cell Adhes. Migr.2020141698110.1080/19336918.2020.173389232090682
     [Google Scholar]
  38. LiX. BaoC. MaZ. XuB. YingX. LiuX. ZhangX. Perfluorooctanoic acid stimulates ovarian cancer cell migration, invasion via ERK/NF-κB/MMP-2/-9 pathway.Toxicol. Lett.2018294445010.1016/j.toxlet.2018.05.00929753068
     [Google Scholar]
  39. HaS.H. KwonK.M. ParkJ.Y. AbekuraF. LeeY.C. ChungT.W. HaK.T. ChangH.W. ChoS.H. KimJ.S. KimC.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.201912069810981910.1002/jcb.2826130525244
     [Google Scholar]
  40. ZhangW. WangF. XuP. MiaoC. ZengX. CuiX. LuC. XieH. YinH. ChenF. MaJ. GaoS. FuZ. Perfluorooctanoic acid stimulates breast cancer cells invasion and up-regulates matrix metalloproteinase-2/-9 expression mediated by activating NF-κB.Toxicol. Lett.2014229111812510.1016/j.toxlet.2014.06.00424960061
     [Google Scholar]
  41. JiangH. ZhouZ. JinS. XuK. ZhangH. XuJ. SunQ. WangJ. XuJ. PRMT 9 promotes hepatocellular carcinoma invasion and metastasis via activating PI 3K/Akt/ GSK ‐3β/Snail signaling.Cancer Sci.201810951414142710.1111/cas.1359829603830
     [Google Scholar]
  42. IdiiatullinaE. Al-AzabM. WalanaW. PavlovV. LiuB. 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.202113411113610.1016/j.biopha.2020.11113633341042
     [Google Scholar]
  43. EsfahanianN. ShakibaY. NikbinB. SorayaH. Maleki-DizajiN. Ghazi-KhansariM. GarjaniA. Effect of metformin on the proliferation, migration, and MMP-2 and -9 expression of human umbilical vein endothelial cells.Mol. Med. Rep.2012541068107410.3892/mmr.2012.75322246099
     [Google Scholar]
  44. SeralaK. SteenkampP. MampuruL. PrinceS. PoopediK. MbazimaV. in vitro antimetastatic activity of Momordica balsamina crude acetone extract in HT -29 human colon cancer cells.Environ. Toxicol.202136112196220510.1002/tox.2333334272816
     [Google Scholar]
/content/journals/cmp/10.2174/1874467217666230915125622
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PF-04449913 Inhibits Proliferation and Metastasis of Colorectal Cancer Cells by Down-regulating MMP9 Expression through the ERK/p65 Pathway
Curr Mol Pharmacol 17, e150923221164 (2024); https://doi.org/10.2174/1874467217666230915125622
/content/journals/cmp/10.2174/1874467217666230915125622
/content/journals/cmp/10.2174/1874467217666230915125622
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  • Article Type:     Research Article
Keyword(s): Colorectal cancer; ERK/p65 pathway; Metastasis; MMP9 expression; PF-04449913; Proliferation

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