Skip to main content
SpringerLink
Log in

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

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

One of the most prevalent malignancies is esophageal squamous cell carcinoma (ESCC), which is associated with high morbidity and mortality. Substance P (SP), as one of the peptides released from sensory nerves, causes the enhancement of cellular excitability through the activation of the neurokinin-1 (NK1) receptor in several human tumor cells. Aprepitant, a specific, potent, and long-acting NK1 receptor antagonist, is considered as a novel agent to inhibit proliferation and induce apoptosis in malignant cells. Since the antitumor mechanism of aprepitant in ESCC is not completely understood, we conducted this study and found that aprepitant induced growth inhibition of KYSE-30 cells and arrested cells in the G2/M phase of the cell cycle. Aprepitant also caused apoptotic cell death and inhibited activation of the PI3K/Akt axis and its downstream effectors, including NF-κB in KYSE-30 cells. Besides, quantitative real-time (qRT)-PCR analysis showed a significant down-regulation of NF-κB target genes in KYSE-30 cells, indicating a probable NF-κB-dependent mechanism involved in aprepitant cytotoxicity. Thus, the present study recommends that SP/NK1R system might, therefore, be considered as an emerging and promising therapeutic strategy against ESCC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Gregson EM, Bornschein J, Fitzgerald RC (2016) Genetic progression of Barrett’s oesophagus to oesophageal adenocarcinoma. Br J Cancer 115(4):403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Pennathur A, Gibson MK, Jobe BA, Luketich JD (2013) Oesophageal carcinoma. Lancet 381(9864):400–412

    Article  PubMed  Google Scholar 

  3. Kauppila JH, Mattsson F, Brusselaers N, Lagergren J (2018) Prognosis of oesophageal adenocarcinoma and squamous cell carcinoma following surgery and no surgery in a nationwide Swedish cohort study. BMJ Open 8(5):e021495

    Article  PubMed  PubMed Central  Google Scholar 

  4. Sudo T, Nishida R, Kawahara A, Saisho K, Mimori K, Yamada A et al (2017) Clinical impact of tumor-infiltrating lymphocytes in esophageal squamous cell carcinoma. Ann Surg Oncol 24(12):3763–3770

    Article  PubMed  Google Scholar 

  5. Toh Y, Egashira A, Yamamoto M (2013) Epigenetic alterations and their clinical implications in esophageal squamous cell carcinoma. Gen Thorac Cardiovasc Surg 61(5):262–269

    Article  PubMed  Google Scholar 

  6. Jin Z, Olaru A, Yang J, Sato F, Cheng Y, Kan T et al (2007) Hypermethylation of tachykinin-1 is a potential biomarker in human esophageal cancer. Clin Cancer Res 13(21):6293–6300

    Article  CAS  PubMed  Google Scholar 

  7. Misawa K, Kanazawa T, Misawa Y, Imai A, Uehara T, Mochizuki D et al (2013) Frequent promoter hypermethylation of tachykinin-1 and tachykinin receptor type 1 is a potential biomarker for head and neck cancer. J Cancer Res Clin Oncol 139(5):879–889

    Article  CAS  PubMed  Google Scholar 

  8. Pennefather JN, Lecci A, Candenas ML, Patak E, Pinto FM, Maggi CA (2004) Tachykinins and tachykinin receptors: a growing family. Life Sci 74(12):1445–1463

    Article  CAS  PubMed  Google Scholar 

  9. Javid H, Mohammadi F, Zahiri E, Hashemy SI (2019) The emerging role of substance P/neurokinin-1 receptor signaling pathways in growth and development of tumor cells. J Physiol Biochem. 165(10):5606–5611

    Google Scholar 

  10. Page NM (2005) New challenges in the study of the mammalian tachykinins. Peptides 26(8):1356–1368

    Article  CAS  PubMed  Google Scholar 

  11. Mantyh PW (2002) Neurobiology of substance P and the NK1 receptor. J Clin Psychiatry 63:6–10

    CAS  PubMed  Google Scholar 

  12. Legi A, Robinson P (2019) Role of substance P in pathogenesis of chemotherapy associated cardiotoxicity. Circ Res. 125(1):A185

    Google Scholar 

  13. Munoz M, Covenas R (2013) Involvement of substance P and the NK-1 receptor in cancer progression. Peptides 48:1–9

    Article  CAS  PubMed  Google Scholar 

  14. Covenas R, Munoz M (2014) Cancer progression and substance P. Histol Histopathol 29(7):881–890

    CAS  PubMed  Google Scholar 

  15. Davoodian M, Boroumand N, Bahar MM, Jafarian AH, Asadi M, Hashemy SI (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

    Article  CAS  PubMed  Google Scholar 

  16. Gharaee N, Pourali L, Jafarian AH, Hashemy SI (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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  19. Munoz M, Covenas R (2010) Neurokinin-1 receptor: a new promising target in the treatment of cancer. Discov Med 10(53):305–313

    PubMed  Google Scholar 

  20. Muñoz M, Coveñas R (2015) Targeting NK-1 receptors to prevent and treat pancreatic cancer: a new therapeutic approach. Cancers 7(3):1215–1232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Dando TM, Perry CM (2004) Aprepitant. Drugs 64(7):777–794

    Article  CAS  PubMed  Google Scholar 

  22. 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 

  23. Jordan K, Jahn F, Aapro M (2015) Recent developments in the prevention of chemotherapy-induced nausea and vomiting (CINV): a comprehensive review. Ann Oncol 26(6):1081–1090

    Article  CAS  PubMed  Google Scholar 

  24. MUñOz M, González-Ortega A, Salinas-Martín MV, Carranza A, Garcia-Recio S, Almendro V, et al. The neurokinin-1 receptor antagonist aprepitant is a promising candidate for the treatment of breast cancer. Int J Oncol. 2014;45(4):1658–1672.

  25. Muñoz M, González-Ortega A, Rosso M, Robles-Frias MJ, Carranza A, Salinas-Martín MV 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  CAS  PubMed  Google Scholar 

  26. Robinson P, Taffet G, Engineer N, Khumbatta M, Firozgary B, Reynolds C et al (2015) Substance P receptor antagonism. BioMed Res Int. https://doi.org/10.1155/2015/495704

    Article  PubMed  PubMed Central  Google Scholar 

  27. Bayati S, Bashash D, Ahmadian S, Safaroghli-Azar A, Alimoghaddam K, Ghavamzadeh A et al (2016) Inhibition of tachykinin NK1 receptor using aprepitant induces apoptotic cell death and G1 arrest through Akt/p53 axis in pre-B acute lymphoblastic leukemia cells. Eur J Pharmacol 791:274–283

    Article  CAS  PubMed  Google Scholar 

  28. Yamaguchi K, Kumakura S, Murakami T, Someya A, Inada E, Nagaoka I (2017) Ketamine suppresses the substance P-induced production of IL-6 and IL-8 by human U373MG glioblastoma/astrocytoma cells. Int J Mol Med 39(3):687–692

    Article  CAS  PubMed  Google Scholar 

  29. Bashash D, Safaroghli-Azar A, Bayati S, Razani E, Pourbagheri-Sigaroodi A, Gharehbaghian A et al (2018) Neurokinin-1 receptor (NK1R) inhibition sensitizes APL cells to anti-tumor effect of arsenic trioxide via restriction of NF-κB axis: Shedding new light on resistance to Aprepitant. Int J Biochem Cell Biol 103:105–114

    Article  CAS  PubMed  Google Scholar 

  30. Dong J, Feng F, Xu G, Zhang H, Hong L, Yang J (2015) Elevated SP/NK-1R in esophageal carcinoma promotes esophageal carcinoma cell proliferation and migration. Gene 560(2):205–210

    Article  CAS  PubMed  Google Scholar 

  31. Munoz M, Covenas R, Esteban F, Redondo M (2015) The substance P/NK-1 receptor system: NK-1 receptor antagonists as anti-cancer drugs. J Biosci 40(2):441–463

    Article  CAS  PubMed  Google Scholar 

  32. O’brien J, Wilson I, Orton T, Pognan F (2000) Investigation of the Alamar Blue (resazurin) fluorescent dye for the assessment of mammalian cell cytotoxicity. Eur J Biochem. 267(17):5421–5426

    Article  PubMed  Google Scholar 

  33. Sharifi S, Barar J, Hejazi MS, Samadi N (2014) Roles of the Bcl-2/Bax ratio, caspase-8 and 9 in resistance of breast cancer cells to paclitaxel. Asian Pac J Cancer Prev 15(20):8617–8622

    Article  PubMed  Google Scholar 

  34. Sharifi AM, Eslami H, Larijani B, Davoodi J (2009) Involvement of caspase-8,-9, and-3 in high glucose-induced apoptosis in PC12 cells. Neurosci Lett 459(2):47–51

    Article  CAS  PubMed  Google Scholar 

  35. Li H, Gao Q, Guo L, Lu SH (2011) The PTEN/PI3K/Akt pathway regulates stem-like cells in primary esophageal carcinoma cells. Cancer Biol Ther 11(11):950–958

    Article  CAS  PubMed  Google Scholar 

  36. Liu B, Wang C, Chen P, Cheng B, Cheng Y (2018) RACKI induces chemotherapy resistance in esophageal carcinoma by upregulating the PI3K/AKT pathway and Bcl-2 expression. OncoTargets Therapy 11:211

    Article  PubMed  PubMed Central  Google Scholar 

  37. Akazawa T, Kwatra SG, Goldsmith LE, Richardson MD, Cox EA, Sampson JH et al (2009) A constitutively active form of neurokinin 1 receptor and neurokinin 1 receptor-mediated apoptosis in glioblastomas. J Nurochem 109(4):1079–1086

    Article  CAS  Google Scholar 

  38. Vara JÁF, Casado E, de Castro J, Cejas P, Belda-Iniesta C, González-Barón M (2004) PI3K/Akt signalling pathway and cancer. Cancer Treatt Rev 30(2):193–204

    Article  CAS  Google Scholar 

  39. Dolcet X, Llobet D, Pallares J, Matias-Guiu X (2005) NF-kB in development and progression of human cancer. Virchows Arch 446(5):475–482

    Article  CAS  PubMed  Google Scholar 

  40. Yang C-R, Wilson-Van PC, Planchon SM, Wuerzberger-Davis SM, Davis TW, Cuthill S et al (2000) Coordinate modulation of Sp1, NF-kappa B, and p53 in confluent human malignant melanoma cells after ionizing radiation. FASEB J. 14(2):379–390

    Article  CAS  PubMed  Google Scholar 

  41. Vurusaner B, Poli G, Basaga H (2012) Tumor suppressor genes and ROS: complex networks of interactions. Free Radic Biol Med 52(1):7–18

    Article  CAS  PubMed  Google Scholar 

  42. Ebrahimi S, Hashemy SI (2019) MicroRNA-mediated redox regulation modulates therapy resistance in cancer cells: clinical perspectives. Cell Oncol (Dordr) 42(2):131–141

    Article  CAS  Google Scholar 

  43. Ebrahimi S, Soltani A, Hashemy SI (2018) Oxidative stress in cervical cancer pathogenesis and resistance to therapy. J Cell Biochem. 120(5):6868–6877

    Article  CAS  Google Scholar 

  44. Singh D, Joshi DD, Hameed M, Qian J, Gascón P, Maloof PB 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 97(1):388–393

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  46. Debeljuk L (2006) Tachykinins and ovarian function in mammals. Peptides 27(4):736–742

    Article  CAS  PubMed  Google Scholar 

  47. Newton S, Walker A, Page N, editors. Stimulation of PKC [beta] II-dependent ERK1/2 signalling by endokinin B and substance P may cause gene transcription via the tachykinin NK1 receptor in astrocytoma cells. Soc Endocrinol BES 2009; 2009: BioScientifica.

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

    PubMed  Google Scholar 

  49. Muñoz M, Coveñas R (2019) Neurokinin-1 receptor antagonists as anticancer drugs. Lett Drug Des Discov 16(10):1110–1129

    Article  CAS  Google Scholar 

  50. Alenzi FQ, Wyse RK, Altamimi WG (2004) Apoptosis as a tool for therapeutic agents in haematological diseases. Expert Opin Biol Therapy 4(3):407–420

    Article  CAS  Google Scholar 

  51. Afshari AR, Jalili-Nik M, Soukhtanloo M, Ghorbani A, Sadeghnia HR, Mollazadeh H et al (2019) Auraptene-induced cytotoxicity mechanisms in human malignant glioblastoma (U87) cells: role of reactive oxygen species (ROS). EXCLI J 18:576–590

    PubMed  PubMed Central  Google Scholar 

  52. Viatour P, Merville M-P, Bours V, Chariot A (2005) Phosphorylation of NF-κB and IκB proteins: implications in cancer and inflammation. Trends Biochem Sci 30(1):43–52

    Article  CAS  PubMed  Google Scholar 

  53. Yamamoto Y, Gaynor RB (2004) IκB kinases: key regulators of the NF-κB pathway. Trends Biochem Sci 29(2):72–79

    Article  CAS  PubMed  Google Scholar 

  54. Bai D, Ueno L, Vogt PK (2009) Akt-mediated regulation of NFκB and the essentialness of NFκB for the oncogenicity of PI3K and Akt. Intl J Cancer 125(12):2863–2870

    Article  CAS  Google Scholar 

  55. Wee KB, Aguda BD (2006) Akt versus p53 in a network of oncogenes and tumor suppressor genes regulating cell survival and death. Biophys J 91(3):857–865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Prasad S, Gupta SC, Tyagi AK (2017) Reactive oxygen species (ROS) and cancer: role of antioxidative nutraceuticals. Cancer Lett 387:95–105

    Article  CAS  PubMed  Google Scholar 

  57. Ju KD, Lim JW, Kim KH, Kim H (2011) Potential role of NADPH oxidase-mediated activation of Jak2/Stat3 and mitogen-activated protein kinases and expression of TGF-β1 in the pathophysiology of acute pancreatitis. Inflamm Res 60(8):791–800

    Article  CAS  PubMed  Google Scholar 

  58. Vaquero EC, Edderkaoui M, Pandol SJ, Gukovsky I, Gukovskaya AS (2004) Reactive oxygen species produced by NAD (P) H oxidase inhibit apoptosis in pancreatic cancer cells. J Biol Chem 279(33):34643–34654

    Article  CAS  PubMed  Google Scholar 

  59. Afshari AR, Roshan MK, Soukhtanloo M, Ghorbani A, Rahmani F, Jalili-Nik M et al (2019) Cytotoxic effects of auraptene against a human malignant glioblastoma cell line. Avic J Phytomed 9(4):334

    Google Scholar 

Download references

Acknowledgements

This work is a part of Hossein Javid’s PhD thesis, which was financially granted by the Research Council at Mashhad University of Medical Sciences (Grant Number: 961738)

Author information

Authors and Affiliations

  1. Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Hossein Javid, Farnaz Zahedi Avval & Seyed Isaac Hashemy

  2. Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Hossein Javid

  3. Department of Clinical Biochemistry, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran

    Jahanbakhsh Asadi

  4. Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran

    Amir R. Afshari

  5. Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

    Seyed Isaac Hashemy

Authors
  1. Hossein Javid
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jahanbakhsh Asadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Farnaz Zahedi Avval
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amir R. Afshari
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Seyed Isaac Hashemy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Seyed Isaac Hashemy.

Ethics declarations

Conflict of interests

The authors declare there is not any conflict of interest related to the publication of this article.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Javid, H., Asadi, J., Zahedi Avval, F. et al. 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. Mol Biol Rep 47, 2253–2263 (2020). https://doi.org/10.1007/s11033-020-05330-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-020-05330-9

Keywords

Search

Navigation