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The substance P/ neurokinin-1 receptor signaling pathway mediates metastasis in human colorectal SW480 cancer cells

Abstract

Background

The substance P (SP)/neurokinin-1 receptor (NK1R) system, a critical metastatic signaling pathway, can be targeted by substance P antagonists to prevent its cancer-progressive impacts. In the current study, we aimed to investigate the carcinogenic activity of the SP/NK1R system in human SW480 colorectal cancer cells and study the antagonistic impact of aprepitant (AP) by measuring MMP-2 and MMP-9 enzymatic activity.

Methods

Different concentrations of SP, alone or mixed by AP, were utilized to treat SW480 cells to investigate the cells’ viability and metastasis by applying Resazurin and Gelatin Zymography methods, respectively. The cells’ metastatic response was analyzed by measuring the MMP-2 and MMP-9 in transcriptional and translational levels. Finally, the Scratch assay was carried out to evaluate the cells’ metastatic response following the SP/AP treatment.

Results

A significant metastatic activity was observed in SW480 cells following incubation with the increasing SP doses by detecting MMP-2/MMP-9 enzyme activity, genes overexpression, and enhanced cell migration. This is while the AP treatment meaningfully diminished all the SP-mediated metastatic effects (p-Value < 0.001).

Conclusions

According to the results, the SP/NKR1 signaling pathway can be considered one of the main metastatic effectors in human colorectal cancer. Therefore, AP might be suggested to be used as the SP antagonist and an efficient anti-metastatic drug.

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References

  1. Yokota J (2000) Tumor progression and metastasis. Carcinogenesis 21(3):497–503

    CAS  Article  Google Scholar 

  2. Gao D et al (2018) Metastatic tumor cells–genotypes and phenotypes. Front biology 13(4):277–286

    CAS  Article  Google Scholar 

  3. Bower JJ et al (2017) Patterns of cell cycle checkpoint deregulation associated with intrinsic molecular subtypes of human breast cancer cells. NPJ breast cancer 3(1):1–12

    CAS  Article  Google Scholar 

  4. Alberts B et al (2002) The molecular basis of cancer-cell behavior, in Molecular Biology of the Cell. 4th edition. Garland Science

  5. Hashemian P et al (2020) The Role of Tachykinins in the Initiation and Progression of Gastrointestinal Cancers: A Review.International Journal of Cancer Management, 13(5)

  6. Pennefather JN et al (2004) Tachykinins and tachykinin receptors: a growing family. Life Sci 74(12):1445–1463

    CAS  Article  Google Scholar 

  7. Palma C (2006) Tachykinins and their receptors in human malignancies. Curr Drug Targets 7(8):1043–1052

    CAS  Article  Google Scholar 

  8. Rogers DF et al (1988) Effects and interactions of sensory neuropeptides on airway microvascular leakage in guinea-pigs. Br J Pharmacol 95(4):1109

    CAS  Article  Google Scholar 

  9. Mayordomo C et al (2012) Targeting of substance P induces cancer cell death and decreases the steady state of EGFR and Her2. J Cell Physiol 227(4):1358–1366

    CAS  Article  Google Scholar 

  10. Khorasani S et al (2020) The immunomodulatory effects of tachykinins and their receptors. J Cell Biochem 121(5–6):3031–3041

    CAS  Article  Google Scholar 

  11. Ebrahimi S et al (2020) New insight into the role of substance P/neurokinin-1 receptor system in breast cancer progression and its crosstalk with microRNAs.Clin Genet,

  12. Javid H et al (2019) The emerging role of substance P/neurokinin-1 receptor signaling pathways in growth and development of tumor cells. J Physiol Biochem 75(4):415–421

    CAS  Article  Google Scholar 

  13. Davoodian M et al (2019) Evaluation of serum level of substance P and tissue distribution of NK-1 receptor in breast cancer. Mol Biol Rep 46(1):1285–1293

    CAS  Article  Google Scholar 

  14. Gharaee N et al (2018) Evaluation of serum level of substance P and tissue distribution of NK-1 receptor in endometrial cancer. Mol Biol Rep 45(6):2257–2262

    CAS  Article  Google Scholar 

  15. Douglas SD, Leeman SE (2011) Neurokinin-1 receptor: functional significance in the immune system in reference to selected infections and inflammation, vol 1217. Annals of the New York Academy of Sciences, p 83

  16. Rosso M et al (2008) The NK-1 receptor is expressed in human primary gastric and colon adenocarcinomas and is involved in the antitumor action of L-733,060 and the mitogenic action of substance P on human gastrointestinal cancer cell lines. Tumor Biology 29(4):245–254

    CAS  Article  Google Scholar 

  17. Bigioni M et al (2005) Role of NK-1 and NK-2 tachykinin receptor antagonism on the growth of human breast carcinoma cell line MDA-MB-231. Anti-cancer drugs. 16:1083–108910

  18. Isorna I et al (2020) The substance P and neurokinin-1 receptor system in human thyroid cancer: an immunohistochemical study. Eur J histochemistry: EJH 64(2):3117

    CAS  Article  Google Scholar 

  19. Muñoz M, Coveñas R (2014) Involvement of substance P and the NK-1 receptor in pancreatic cancer. World J Gastroenterol 20(9):2321–2334

    Article  Google Scholar 

  20. Javid H et al (2020) The role of substance P/neurokinin 1 receptor in the pathogenesis of esophageal squamous cell carcinoma through constitutively active PI3K/Akt/NF-κB signal transduction pathways. 47:2253–22633

  21. Mehrabani N et al (2021) The SP/NK1R System-Mediated ROS Generation in GBM Cells through Inhibiting Glutaredoxin Protein. Neurology Research International, 2021

  22. Korfi F et al (2021) The Effect of SP/NK1R on the Expression and Activity of Catalase and Superoxide Dismutase in Glioblastoma Cancer Cells. Biochemistry Research International, 2021: p. 6620708

  23. Ghahremani F et al (2021) Pathogenic role of the SP/ NK1R system in GBM cells through inhibiting the thioredoxin system. Iran J Basic Med Sci 24(4):499–505

    PubMed  PubMed Central  Google Scholar 

  24. Chen X-Y et al (2016) High expression of substance P and its receptor neurokinin-1 receptor in colorectal cancer is associated with tumor progression and prognosis. OncoTargets and therapy 9:3595–3602

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Quintero-Fabián S et al (2019) Role of matrix metalloproteinases in angiogenesis and cancer. Front Oncol 9:1370

    Article  Google Scholar 

  26. Borra RC et al (2009) A simple method to measure cell viability in proliferation and cytotoxicity assays. Brazilian oral research 23(3):255–262

    Article  Google Scholar 

  27. Webb AH et al (2017) Inhibition of MMP-2 and MMP-9 decreases cellular migration, and angiogenesis in in vitro models of retinoblastoma. BMC Cancer 17(1):1–11

    Article  Google Scholar 

  28. Shibuya M (2011) Vascular Endothelial Growth Factor (VEGF) and Its Receptor (VEGFR) Signaling in Angiogenesis: A Crucial Target for Anti- and Pro-Angiogenic Therapies. Genes & cancer 2(12):1097–1105

    Article  Google Scholar 

  29. Paul CD, Mistriotis P, Konstantopoulos K (2017) Cancer cell motility: lessons from migration in confined spaces. Nat Rev Cancer 17(2):131–140

    CAS  Article  Google Scholar 

  30. Muñoz M, Rosso M, Coveñas R (2011) The NK-1 receptor: a new target in cancer therapy. Curr Drug Targets 12(6):909–921

    Article  Google Scholar 

  31. Singh D et al (2000) Increased expression of preprotachykinin-I and neurokinin receptors in human breast cancer cells: implications for bone marrow metastasis. Proc Natl Acad Sci USA 97(1):388–393

    CAS  Article  Google Scholar 

  32. CHIANG I-T et al (2012) Sorafenib inhibits TPA-induced MMP-9 and VEGF expression via suppression of ERK/NF-κB pathway in hepatocellular carcinoma cells. In vivo. 26:671–6814

  33. Ukaji T et al (2017) Inhibition of MMP-2-mediated cellular invasion by NF-κB inhibitor DHMEQ in 3D culture of breast carcinoma MDA-MB-231 cells: A model for early phase of metastasis. Biochem Biophys Res Commun 485(1):76–81

    CAS  Article  Google Scholar 

  34. Laronha H, Caldeira J (2020)Structure and Function of Human Matrix Metalloproteinases.9(5)

  35. Gong H et al (2019) Rho-associated protein kinase (ROCK) promotes proliferation and migration of PC-3 and DU145 prostate cancer cells by targeting LIM kinase 1 (LIMK1) and matrix metalloproteinase-2 (MMP-2). Medical science monitor: international medical journal of experimental and clinical research, 25: p. 3090

  36. Kataoka M et al (1996) Matrix metalloproteinase 2 and 9 in esophageal cancer. Int J Oncol 8(4):773–779

    CAS  PubMed  Google Scholar 

  37. Xie L et al (2010) CD10-bearing fibroblast inhibits matrigel invasive potency of interleukin‐1α‐producing squamous cell carcinoma by diminishing substance P levels in the tumor microenvironment. Cancer Sci 101(12):2570–2578

    CAS  Article  Google Scholar 

  38. Li X et al (2013) Neurotransmitter substance P mediates pancreatic cancer perineural invasion via NK1R in cancer cells. Mol Cancer Res 11(3):294–302

    CAS  Article  Google Scholar 

  39. Humphreys S, Pellissier J, Jones A (2013) Cost-effectiveness of an aprepitant regimen for prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer in the UK. Cancer Manage Res 5:215

    Article  Google Scholar 

  40. Prommer E (2005) Aprepitant (EMEND) the role of substance P in nausea and vomiting. J Pain Palliat Care Pharm 19(3):31–39

    Google Scholar 

  41. Muñoz M, Coveñas R (2016) Neurokinin-1 receptor antagonists as antitumor drugs in gastrointestinal cancer: A new approach. Saudi J Gastroenterol 22(4):260–268

    Article  Google Scholar 

  42. Javid H et al (2021) Aprepitant Promotes Caspase-Dependent Apoptotic Cell Death and G2/M Arrest through PI3K/Akt/NF-κB Axis in Cancer Stem-Like Esophageal Squamous Cell Carcinoma Spheres. BioMed Research International, 2021

  43. Muñoz M, Rosso M (2010) The NK-1 receptor antagonist aprepitant as a broad spectrum antitumor drug. Investig New Drugs 28(2):187–193

    Article  Google Scholar 

  44. Muñoz M et al (2012) The substance P/neurokinin-1 receptor system in lung cancer: focus on the antitumor action of neurokinin-1 receptor antagonists. Peptides 38(2):318–325

    Article  Google Scholar 

  45. Ghahremanloo A et al (2021) Investigation of the role of neurokinin-1 receptor inhibition using aprepitant in the apoptotic cell death through PI3K/akt/NF-κB signal transduction pathways in colon cancer cells. BioMed research international, 2021

  46. Muñoz M et al (2014) The neurokinin-1 receptor antagonist aprepitant is a promising candidate for the treatment of breast cancer. Int J Oncol 45(4):1658–1672

    Article  Google Scholar 

  47. Liu J et al (2018) Rho-Associated Coiled-Coil kinase (ROCK) in molecular regulation of angiogenesis. Theranostics 8(21):6053

    CAS  Article  Google Scholar 

  48. Ebrahimi S, Soltani A, Hashemy SI (2018) Oxidative stress in cervical cancer pathogenesis and resistance to therapy.J Cell Biochem,

  49. Gencer S, Cebeci A, Irmak-Yazicioglu MB (2013) Matrix metalloproteinase gene expressions might be oxidative stress targets in gastric cancer cell lines. Chin J Cancer Res 25(3):322–333

    PubMed  PubMed Central  Google Scholar 

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SIH was responsible for the conceptualization and supervision of the project. All authors contributed to the gathering of data. MG wrote the first draft of the manuscript, and SIH finalized and submitted the paper. All authors have read and approved the final format of the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Seyed Isaac Hashemy MD-PhD.

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Golestaneh, M., Firoozrai, M., Javid, H. et al. The substance P/ neurokinin-1 receptor signaling pathway mediates metastasis in human colorectal SW480 cancer cells. Mol Biol Rep 49, 4893–4900 (2022). https://doi.org/10.1007/s11033-022-07348-7

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  • DOI: https://doi.org/10.1007/s11033-022-07348-7

Keywords

  • Substance P
  • Neurokinin 1 receptor
  • Metastasis
  • Aprepitant
  • Colorectal cancer