Ukr.Biochem.J. 2021; Volume 93, Issue 4, Jul-Aug, pp. 45-54

doi: doi:

Effect of IRAK1/4 inhibitor on IL-1β, IL-6, INF-γ and TNF-α expression in breast cancer cells of several lines

M. Rezaei1, B. Shahouzehi2,4, S. Rahemi1,3, H. Fallah1*, M. Salarkarimi1

1Department of Clinical Biochemistry, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran;
2Cardiovascular Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran;
3Physiology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran;
4Student Research Committee, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran;

Received: 28 July 2020; Accepted: 07 July 2021

Recent studies have shown that inflammation mediated via interleukin-1 receptor-associated kinases (IRAKs) is associated with cancer cells drug resistance. We aimed to evaluate the expression of inflammatory cytokines as the potential mechanism involved in the development of cancer cells resistance to conventional chemotherapy drugs. Breast cancer cells of BT549, BT20 and MB468 lines were treated with IRAK 1/4 inhibitor alone or in combination with chemotherapeutic agents methotrexate and topotecan. Expression of IL-1β, IL-6, TNF-α, and IFN-γ genes was quantified by real-time PCR. It was found that IRAK1/4 inhibitor suppressed IL-1β expression in BT549 cells at most and had minimal effect on IL-6 expression in MB468 cells. For the first time we showed that concomitant use of IRAK1/4 inhibitor with topotecan and methotrexate reduced IL-1β, IFN γ, TNF-α and IL-6 expression in BT-20, BT-549, MB-468 cell lines compared to the controls. It is suggested that specific IRAK inhibitors in combination with conventional chemotherapy can be used in cancer treatment to increase drug sensitivity and decrease the risk of tumor recurrence.

Keywords: , , , ,


  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424. PubMed, CrossRef
  2. Edwardson DW, Boudreau J, Mapletoft J, Lanner C, Kovala AT, Parissenti AM. Inflammatory cytokine production in tumor cells upon chemotherapy drug exposure or upon selection for drug resistance. PLoS One. 2017;12(9):e0183662. PubMed, PubMedCentral, CrossRef
  3. Temian DC, Pop LA, Irimie AI, Berindan-Neagoe I. The Epigenetics of Triple-Negative and Basal-Like Breast Cancer: Current Knowledge. J Breast Cancer. 2018;21(3):233-243. PubMed, PubMedCentral, CrossRef
  4. Anjum F, Razvi N, Masood MA. Breast cancer therapy: a mini review. MOJ Drug Des Develop Ther. 2017;1(2):35-38. CrossRef
  5. Liu FS. Mechanisms of chemotherapeutic drug resistance in cancer therapy–a quick review. Taiwan J Obstet Gynecol. 2009;48(3):239-244. PubMed, CrossRef
  6. Eiró N, González L, González LO, Fernandez-Garcia B, Lamelas ML, Marín L, González-Reyes S, del Casar JM, Vizoso FJ. Relationship between the inflammatory molecular profile of breast carcinomas and distant metastasis development. PLoS One. 2012;7(11):e49047. PubMed, PubMedCentral, CrossRef
  7. Körber MI, Staribacher A, Ratzenböck I, Steger G, Mader RM. NFκB-Associated Pathways in Progression of Chemoresistance to 5-Fluorouracil in an In Vitro Model of Colonic Carcinoma. Anticancer Res. 2016;36(4):1631-1639. PubMed
  8. Wang W, Nag SA,  Zhang R. Targeting the NFκB signaling pathways for breast cancer prevention and therapy. Curr Med Chem. 2015;22(2):264-289.
    PubMed, PubMedCentral, CrossRef
  9. Labbozzetta M, Notarbartolo M, Poma P Can NF-κB Be Considered a Valid Drug Target in Neoplastic Diseases? Our Point of View. Int J Mol Sci. 2020;21(9):3070. PubMed, PubMedCentral, CrossRef
  10. Kawasaki T, Kawai T. Toll-like receptor signaling pathways. Front Immunol. 2014;5:461. PubMed, CrossRef
  11. Liu T, Zhang L, Joo D, Sun SC. NF-κB signaling in inflammation. Signal Transduct Target Ther. 2017;2:17023. PubMed, PubMedCentral, CrossRef
  12. Liu M, Sakamaki T, Casimiro NE, Willmarth NE, Quong AA, Ju X, Ojeifo J, Jiao X, Yeow WS, Katiyar S, Shirley LA, Joyce D, Lisanti MP, Albanese C, Pestell RG. The canonical NF-kappaB pathway governs mammary tumorigenesis in transgenic mice and tumor stem cell expansion. Cancer Res. 2010;70(24):10464-10473. PubMed, PubMedCentral, CrossRef
  13. Rahemi S, Nematollahi-Mahani SN, Rajaie A, Fallah H. Inhibitor of Interleukin-1 Receptor-associated Kinases 1/4, Can Increase the Sensitivity of Breast Cancer Cells to Methotrexate. Int J Mol Cell Med. 2019;8(3):200-209. PubMed, PubMedCentral, CrossRef
  14. Nedeljković M, Damjanović A. Mechanisms of Chemotherapy Resistance in Triple-Negative Breast Cancer-How We Can Rise to the Challenge. Cells. 2019;8(9):957.  PubMed, PubMedCentral, CrossRef, PubMedCentral, CrossRef
  15. Olsen NJ, Spurlock  CF 3rd, Aune TM. Methotrexate induces production of IL-1 and IL-6 in the monocytic cell line U937. Arthritis Res Ther. 2014;16(1):R17. PubMed, PubMedCentral, CrossRef
  16. Nishina N, Kaneko Y, Kameda H, Kuwana M, Takeuchi T. Reduction of plasma IL-6 but not TNF-α by methotrexate in patients with early rheumatoid arthritis: a potential biomarker for radiographic progression. Clin Rheumatol. 2013;32(11):1661-1666. PubMed, CrossRef
  17. Zhang Z, Lin G, Yan Y, Li Y, Hu Y, Wang J, Yin B, Wu Y, Li Z, Yang XP. Transmembrane TNF-alpha promotes chemoresistance in breast cancer cells. Oncogene. 2018;37(25):3456-3470. PubMed, PubMedCentral, CrossRef
  18. Saijo Y, Tanaka M, Miki M, Usui K, Suzuki T, Maemond M, Hong X, Tazawa R, Kikuchi T, Matsushima K, Nukiwa T. Proinflammatory cytokine IL-1 beta promotes tumor growth of Lewis lung carcinoma by induction of angiogenic factors: in vivo analysis of tumor-stromal interaction. J Immunol. 2002;169(1):469-475. PubMed, CrossRef
  19. Gemma A, Takenaka K, Hosoya Y, Matuda K, Seike M, Kurimoto F, Ono Y, Uematsu K, Takeda Y, Hibino S, Yoshimura A, Shibuya M, Kudoh S. Altered expression of several genes in highly metastatic subpopulations of a human pulmonary adenocarcinoma cell line. Eur J Cancer. 2001;37(12):1554-1561. PubMed, CrossRef
  20. Holen I, Lefley DV, Francis SE, Rennicks S, Bradbury S, Coleman RE, Ottewell P. IL-1 drives breast cancer growth and bone metastasis in vivo. Oncotarget. 2016;7(46):75571-75584. PubMed, PubMedCentral, CrossRef
  21. Srivastava R, Geng D, Liu Y, Zheng L, Li Z, Joseph MA, McKenna C, Bansal N, Ochoa A, Davila E. Augmentation of therapeutic responses in melanoma by inhibition of IRAK-1,-4. Cancer Res. 2012;72(23):6209-6216. PubMed, PubMedCentral, CrossRef
  22. Cheng BY, Lau EY, Leung HW, Leung CO, NP Ho  3 , S Gurung  3 , LK Cheng  5 , Lin CH, Lo RC, Ma S, Ng IO, Lee TK. IRAK1 Augments Cancer Stemness and Drug Resistance via the AP-1/AKR1B10 Signaling Cascade in Hepatocellular Carcinoma. Cancer Res. 2018;78(9):2332-2342. PubMed, CrossRef
  23. Jain A, Kaczanowska S, Davila E. IL-1 Receptor-Associated Kinase Signaling and Its Role in Inflammation, Cancer Progression, and Therapy Resistance. Front Immunol. 2014;5:553. PubMed, PubMedCentral, CrossRef
  24. Ni H, Shirazi F, Baladandayuthapani V, Lin H, Kuiatse I, Wang H, Jones RJ, Berkova Z, Hitoshi Y, Ansell SM, Treon SP, Thomas SK, Lee HC, Wang Z, Davis RE, Orlowski RZ. Targeting Myddosome Signaling in Waldenström’s Macroglobulinemia with the Interleukin-1 Receptor-Associated Kinase 1/4 Inhibitor R191. Clin Cancer Res. 2018;24(24):6408-6420. PubMed, PubMedCentral, CrossRef
  25. Bhaumik D, Scott GK, Schokrpur S, Patil CK, Campisi J, Benz CC. Expression of microRNA-146 suppresses NF-kappaB activity with reduction of metastatic potential in breast cancer cells. Oncogene. 2008;27(42):5643-5647. PubMed, PubMedCentral, CrossRef
  26. Yang M, Qin X, Qin G, Zheng X. The role of IRAK1 in breast cancer patients treated with neoadjuvant chemotherapy [Corrigendum]. Onco Targets Ther. 2019;12:5375. PubMed, PubMedCentral, CrossRef

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