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2000
Volume 10, Issue 1
  • ISSN: 2212-697X
  • E-ISSN: 2212-6988

Abstract

Background

The Wnt/beta-catenin pathway is one of the pathways that is deregulated in pancreatic cancer and is reported to be associated with a poor prognosis. This indicates the need for the identification of novel agents to improve the efficacy of current therapy or have an improved efficacy. Therefore, in the present study, we explored the anticancer activity of PNU-74654 alone or in combination with gemcitabine in 2 and 3-dimensional cell culture models of pancreatic cancer.

Methods

The MTT assay was carried out to determine the viability of PC cancerous cells (PCCs), while the cytotoxicity of this agent was evaluated in a 3D cell culture model (spheroid). The effects of PNU-74654 were investigated in established cell migration/invasion assays.

Results

The expression of candidate genes affecting the cell cycle, migration, and Wnt/b-catenin pathway was evaluated at mRNA and/or proteins by RT-PCR or Western blot. PNU-74654 inhibited the cell growth at IC of 122 ± 0.4 umol/L and had a synergistic effect on the antiproliferative properties of gemcitabine by modulating the Wnt pathway. The PNU-74654/gemcitabine combination reduced the migratory and invasiveness of PC cells, compared to control cells, through perturbation of E-cadherin.

Conclusion

Our findings demonstrate the profound antitumor properties of PNU-74654 in models of pancreatic cancer, supporting further studies to evaluate the therapeutic impact of this novel therapy to target the Wnt pathway in the treatment of pancreatic cancer.

© 2024 Bentham Science Publishers
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2024-04-21
2025-10-08

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References

  1. JemalA. SiegelR. WardE. MurrayT. XuJ. ThunM.J. Cancer statistics, 2007.CA Cancer J. Clin.2007571436610.3322/canjclin.57.1.43 17237035
     [Google Scholar]
  2. YeoT.P. HrubanR.H. LeachS.D. Pancreatic cancer.Curr. Probl. Cancer200226417627510.1067/mcn.2002.129579 12399802
     [Google Scholar]
  3. SiegelR. NaishadhamD. JemalA. Cancer statistics, 2013.CA Cancer J. Clin.2013631113010.3322/caac.21166 23335087
     [Google Scholar]
  4. FeldmannG. MaitraA. Molecular genetics of pancreatic ductal adenocarcinomas and recent implications for translational efforts.J. Mol. Diagn.200810211112210.2353/jmoldx.2008.070115 18258927
     [Google Scholar]
  5. JonesS. ZhangX. ParsonsD.W. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses.Science200832158971801180610.1126/science.1164368 18772397
     [Google Scholar]
  6. MorrisJ.P.IV WangS.C. HebrokM. KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma.Nat. Rev. Cancer2010101068369510.1038/nrc2899 20814421
     [Google Scholar]
  7. ZhangY. MorrisJ.P.IV YanW. Canonical Wnt signaling is required for pancreatic carcinogenesis.Cancer Res.201373154909492210.1158/0008‑5472.CAN‑12‑4384 23761328
     [Google Scholar]
  8. MiyamotoY. MaitraA. GhoshB. Notch mediates TGFα-induced changes in epithelial differentiation during pancreatic tumorigenesis.Cancer Cell20033656557610.1016/S1535‑6108(03)00140‑5 12842085
     [Google Scholar]
  9. BermanD.M. KarhadkarS.S. MaitraA. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours.Nature2003425696084685110.1038/nature01972 14520411
     [Google Scholar]
  10. ThayerS.P. di MaglianoM.P. HeiserP.W. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis.Nature2003425696085185610.1038/nature02009 14520413
     [Google Scholar]
  11. Pasca di MaglianoM. BiankinA.V. HeiserP.W. Common activation of canonical Wnt signaling in pancreatic adenocarcinoma.PLoS One2007211e115510.1371/journal.pone.0001155 17982507
     [Google Scholar]
  12. CleversH. NusseR. Wnt/β-catenin signaling and disease.Cell201214961192120510.1016/j.cell.2012.05.012 22682243
     [Google Scholar]
  13. SchwitallaS. FingerleA.A. CammareriP. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties.Cell20131521-2253810.1016/j.cell.2012.12.012 23273993
     [Google Scholar]
  14. PolakisP. Wnt signaling in cancer.Cold Spring Harb. Perspect. Biol.201245a00805210.1101/cshperspect.a008052 22438566
     [Google Scholar]
  15. MaftouhM. BeloA.I. AvanA. Galectin-4 expression is associated with reduced lymph node metastasis and modulation of Wnt/β-catenin signalling in pancreatic adenocarcinoma.Oncotarget20145145335534910.18632/oncotarget.2104 24977327
     [Google Scholar]
  16. MacDonaldB.T. TamaiK. HeX. Wnt/beta-catenin signaling: Components, mechanisms, and diseases.Dev. Cell200917192610.1016/j.devcel.2009.06.016 19619488
     [Google Scholar]
  17. CleversH. Wnt/beta-catenin signaling in development and disease.Cell2006127346948010.1016/j.cell.2006.10.018 17081971
     [Google Scholar]
  18. WuD. PanW. GSK3: A multifaceted kinase in Wnt signaling.Trends Biochem. Sci.201035316116810.1016/j.tibs.2009.10.002 19884009
     [Google Scholar]
  19. JacobsK.M. BhaveS.R. FerraroD.J. JaboinJ.J. HallahanD.E. ThotalaD. GSK-3: A bifunctional role in cell death pathways.Int. J. Cell Biol.2012201211110.1155/2012/930710 22675363
     [Google Scholar]
  20. GoughN.R. Focus issue: Wnt and β-catenin signaling in development and disease.Sci. Signal.20125206eg210.1126/scisignal.2002806 22234609
     [Google Scholar]
  21. GordonM.D. NusseR. Wnt signaling: Multiple pathways, multiple receptors, and multiple transcription factors.J. Biol. Chem.200628132224292243310.1074/jbc.R600015200 16793760
     [Google Scholar]
  22. SatelliA. RaoP.S. ThirumalaS. RaoU.S. Galectin‐4 functions as a tumor suppressor of human colorectal cancer.Int. J. Cancer2011129479980910.1002/ijc.25750 21064109
     [Google Scholar]
  23. LealL.F. BuenoA.C. GomesD.C. AbduchR. de CastroM. AntoniniS.R. Inhibition of the Tcf/beta-catenin complex increases apoptosis and impairs adrenocortical tumor cell proliferation and adrenal steroidogenesis.Oncotarget2015640430164303210.18632/oncotarget.5513 26515592
     [Google Scholar]
  24. TrossetJ.Y. DalvitC. KnappS. Inhibition of protein–protein interactions: The discovery of druglike β‐catenin inhibitors by combining virtual and biophysical screening.Proteins2006641606710.1002/prot.20955 16568448
     [Google Scholar]
  25. RovithiM. AvanA. FunelN. Development of bioluminescent chick chorioallantoic membrane (CAM) models for primary pancreatic cancer cells: A platform for drug testing.Sci. Rep.2017714468610.1038/srep44686 28304379
     [Google Scholar]
  26. AvanA. QuintK. NicoliniF. Enhancement of the antiproliferative activity of gemcitabine by modulation of c-Met pathway in pancreatic cancer.Curr. Pharm. Des.201319594095010.2174/138161213804547312 22973962
     [Google Scholar]
  27. MaftouhM. AvanA. SciarrilloR. Synergistic interaction of novel lactate dehydrogenase inhibitors with gemcitabine against pancreatic cancer cells in hypoxia.Br. J. Cancer2014110117218210.1038/bjc.2013.681 24178759
     [Google Scholar]
  28. NedaeiniaR. SharifiM. AvanA. Locked nucleic acid anti-miR-21 inhibits cell growth and invasive behaviors of a colorectal adenocarcinoma cell line: LNA-anti-miR as a novel approach.Cancer Gene Ther.201623824625310.1038/cgt.2016.25 27364574
     [Google Scholar]
  29. MollazadehS. MehrabadiS. HassanianS.M. Photodynamic therapy as a desirable approach in the treatment of colorectal cancer, with special focus on photodynamic nanotherapeutics in immunotherapy.Curr. Med. Chem.20243110.2174/0109298673267788231208073338 38275066
     [Google Scholar]
  30. MaftouhM. AvanA. FunelN. miR-211 modulates gemcitabine activity through downregulation of ribonucleotide reductase and inhibits the invasive behavior of pancreatic cancer cells.Nucleosides Nucleotides Nucleic Acids2014334-638439310.1080/15257770.2014.891741 24940696
     [Google Scholar]
  31. AntoR.J. MukhopadhyayA. DenningK. AggarwalB.B. Curcumin (diferuloylmethane) induces apoptosis through activation of caspase-8, BID cleavage and cytochrome c release: Its suppression by ectopic expression of Bcl-2 and Bcl-xl.Carcinogenesis200223114315010.1093/carcin/23.1.143 11756235
     [Google Scholar]
  32. AvanA. CarettiV. FunelN. Crizotinib inhibits metabolic inactivation of gemcitabine in c-Met-driven pancreatic carcinoma.Cancer Res.201373226745675610.1158/0008‑5472.CAN‑13‑0837 24085787
     [Google Scholar]
  33. AvanA. CreaF. PaolicchiE. Molecular mechanisms involved in the synergistic interaction of the EZH2 inhibitor 3-deazaneplanocin A with gemcitabine in pancreatic cancer cells.Mol. Cancer Ther.20121181735174610.1158/1535‑7163.MCT‑12‑0037 22622284
     [Google Scholar]
  34. AvanA. AvanA. Le LargeT.Y.S. AKT1 and SELP polymorphisms predict the risk of developing cachexia in pancreatic cancer patients.PLoS One201499e10805710.1371/journal.pone.0108057 25238546
     [Google Scholar]
  35. VoronkovA. KraussS. Wnt/beta-catenin signaling and small molecule inhibitors.Curr. Pharm. Des.201319463466410.2174/138161213804581837 23016862
     [Google Scholar]
  36. HuC.J. WangL.Y. ChodoshL.A. KeithB. SimonM.C. Differential roles of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α in hypoxic gene regulation.Mol. Cell. Biol.200323249361937410.1128/MCB.23.24.9361‑9374.2003 14645546
     [Google Scholar]
  37. KolligsF.T. BommerG. GökeB. Wnt/beta-catenin/tcf signaling: A critical pathway in gastrointestinal tumorigenesis.Digestion200266313114410.1159/000066755 12481159
     [Google Scholar]
  38. RashidM. ZadehL.R. BaradaranB. Up-down regulation of HIF-1α in cancer progression.Gene202179814579610.1016/j.gene.2021.145796 34175393
     [Google Scholar]
  39. ChienT.L. WuY.C. LeeH.L. PNU-74654 induces cell cycle arrest and inhibits EMT progression in pancreatic.Medicina 2023599153110.3390/medicina59091531 37763649
     [Google Scholar]
  40. YaoH. AshiharaE. MaekawaT. Targeting the Wnt/β-catenin signaling pathway in human cancers.Expert Opin. Ther. Targets201115787388710.1517/14728222.2011.577418 21486121
     [Google Scholar]
  41. PolakisP. Drugging Wnt signalling in cancer.EMBO J.201231122737274610.1038/emboj.2012.126 22617421
     [Google Scholar]
  42. DihlmannS. von Knebel DoeberitzM. Wnt/β-catenin-pathway as a molecular target for future anti-cancer therapeutics.Int. J. Cancer2005113451552410.1002/ijc.20609 15472907
     [Google Scholar]
  43. MoonR.T. KohnA.D. FerrariG.V.D. KaykasA. WNT and β-catenin signalling: Diseases and therapies.Nat. Rev. Genet.20045969170110.1038/nrg1427 15372092
     [Google Scholar]
  44. NazariS.E. Khalili-TanhaN. MehrabadiS. The effects of Trigonella Foenum-graecum L. on post-surgical adhesion band formation.Lett. Drug Des. Discov.20242181400140510.2174/1570180820666230417100810
     [Google Scholar]
  45. ZengG. GerminaroM. MicsenyiA. Aberrant Wnt/beta-catenin signaling in pancreatic adenocarcinoma.Neoplasia20068427928910.1593/neo.05607 16756720
     [Google Scholar]
  46. BiliranH.Jr WangY. BanerjeeS. Overexpression of cyclin D1 promotes tumor cell growth and confers resistance to cisplatin-mediated apoptosis in an elastase-myc transgene-expressing pancreatic tumor cell line.Clin. Cancer Res.200511166075608610.1158/1078‑0432.CCR‑04‑2419 16115953
     [Google Scholar]
  47. YuQ. GengY. SicinskiP. Specific protection against breast cancers by cyclin D1 ablation.Nature200141168411017102110.1038/35082500 11429595
     [Google Scholar]
  48. HallM. PetersG. Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer.Adv. Cancer Res.1996686710810.1016/S0065‑230X(08)60352‑8 8712071
     [Google Scholar]
  49. YamamotoM. TamakawaS. YoshieM. YaginumaY. OgawaK. Neoplastic hepatocyte growth associated with cyclin D1 redistribution from the cytoplasm to the nucleus in mouse hepatocarcinogenesis.Mol. Carcinog.2006451290191310.1002/mc.20204 17013836
     [Google Scholar]
  50. KornmannM. IshiwataT. ItakuraJ. TangvoranuntakulP. BegerH.G. KorcM. Increased cyclin D1 in human pancreatic cancer is associated with decreased postoperative survival.Oncology199855436336910.1159/000011879 9663429
     [Google Scholar]
  51. BachmannK. NeumannA. HinschA. Cyclin D1 is a strong prognostic factor for survival in pancreatic cancer: Analysis of CD G870A polymorphism, FISH and immunohistochemistry.J. Surg. Oncol.2015111331632310.1002/jso.23826 25470788
     [Google Scholar]
  52. ChungD.C. BrownS.B. Graeme-CookF. Overexpression of cyclin D1 occurs frequently in human pancreatic endocrine tumors.J. Clin. Endocrinol. Metab.200085114373437810.1210/jc.85.11.4373 11095482
     [Google Scholar]
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PNU-74654 Enhanced the Antiproliferative Activity of Gemcitabine by Targeting Wnt/β-Catenin Pathway in Pancreatic Cancer
Clinical Cancer Drugs 10, e2212697X293676 (2024); https://doi.org/10.2174/012212697X293676240916114229
/content/journals/ccand/10.2174/012212697X293676240916114229
/content/journals/ccand/10.2174/012212697X293676240916114229
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  • Article Type:     Research Article
Keyword(s): gemcitabine; mRNA; Pancreatic cancer; PNU-74654; RT-PCR; Wnt pathway

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