Skip to main content

Advertisement

SpringerLink
Log in

IL-8 regulates the doxorubicin resistance of colorectal cancer cells via modulation of multidrug resistance 1 (MDR1)

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Cytokines play important roles in tumorigenesis and progression of cancer cells, while their functions in drug resistance remain to be illustrated. We successfully generated doxorubicin (Dox)-resistant CRC HCT-116 and SW480 cells (namely HCT-116/Dox and SW480/Dox, respectively). Cytokine expression analysis revealed that IL-8, while not FGF-2, EGF, TGF-β, IL-6, or IL-10, was significantly increased in Dox-resistant CRC cells as compared with their corresponding parental cells. Targeted inhibition of IL-8 via siRNAs or its inhibitor reparixin can increase the Dox sensitivity of HCT-116/Dox and SW480/Dox cells. The si-IL-8 can decrease the mRNA and protein expression of multidrug resistance 1 (MDR1, encoded by ABCB1), while has no effect on the expression of multidrug resistance-associated protein 1 (ABCC1), in CRC Dox-resistant cells. IL-8 can increase the phosphorylation of p65 and then upregulate the binding between p65 and promoter of ABCB1. BAY 11-7082, the inhibitor of NF-κB, suppressed the recombination IL-8 (rIL-8) induced upregulation of ABCB1. It confirmed that NF-κB is involved in IL-8-induced upregulation of ABCB1. rIL-8 also increased the phosphorylation of IKK-β, which can further activate NF-κB, while specific inhibitor of IKK-β (ACHP) can reverse rIL-8-induced phosphorylation of p65 and upregulation of MDR1. These results suggested that IL-8 regulates the Dox resistance of CRC cells via modulation of MDR1 through IKK-β/p65 signals. The targeted inhibition of IL-8 might be an important potential approach to overcome the clinical Dox resistance in CRC patients.

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

Similar content being viewed by others

References

  1. Benoy IH, Salgado R, Van Dam P, Geboers K, Van Marck E, Scharpe S, Vermeulen PB, Dirix LY (2004) Increased serum interleukin-8 in patients with early and metastatic breast cancer correlates with early dissemination and survival. Clin Cancer Res 10:7157–7162

    Article  PubMed  CAS  Google Scholar 

  2. Cascorbi I (2006) Role of pharmacogenetics of ATP-binding cassette transporters in the pharmacokinetics of drugs. Pharmacol Ther 112:457–473

    Article  PubMed  CAS  Google Scholar 

  3. Colombo V, Lupi M, Falcetta F, Forestieri D, D’Incalci M, Ubezio P (2011) Chemotherapeutic activity of silymarin combined with doxorubicin or paclitaxel in sensitive and multidrug-resistant colon cancer cells. Cancer Chemother Pharmacol 67:369–379

    Article  PubMed  CAS  Google Scholar 

  4. De Larco JE, Wuertz BR, Furcht LT (2004) The potential role of neutrophils in promoting the metastatic phenotype of tumors releasing interleukin-8. Clin Cancer Res 10:4895–4900

    Article  PubMed  Google Scholar 

  5. Fidler MM, Soerjomataram I, Bray F (2016) A global view on cancer incidence and national levels of the human development index. Int J Cancer 139:2436–2446

    Article  PubMed  CAS  Google Scholar 

  6. Gottesman MM, Fojo T, Bates SE (2002) Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer 2:48–58

    Article  PubMed  CAS  Google Scholar 

  7. Huang D, Ding Y, Zhou M, Rini BI, Petillo D, Qian CN, Kahnoski R, Futreal PA, Furge KA, Teh BT (2010) Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma. Cancer Res 70:1063–1071

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Karin M, Greten FR (2005) NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 5:749–759

    Article  PubMed  CAS  Google Scholar 

  9. Lee YS, Choi D, Kim NY, Yang S, Jung E, Hong M, Yang D, Lenz HJ, Hong YK (2014) CXCR2 inhibition enhances sulindac-mediated suppression of colon cancer development. Int J Cancer 135:232–237

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Liptrott NJ, Owen A (2011) The role of cytokines in the regulation of drug disposition: extended functional pleiotropism? Expert Opin Drug Metab Toxicol 7:341–352

    Article  PubMed  CAS  Google Scholar 

  11. Longley DB, Johnston PG (2005) Molecular mechanisms of drug resistance. J Pathol 205:275–292

    Article  PubMed  CAS  Google Scholar 

  12. Lurje G, Zhang W, Schultheis AM, Yang D, Groshen S, Hendifar AE, Husain H, Gordon MA, Nagashima F, Chang HM, Lenz HJ (2008) Polymorphisms in VEGF and IL-8 predict tumor recurrence in stage III colon cancer. Ann Oncol 19:1734–1741

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Min J, Liu L, Li X, Jiang J, Wang J, Zhang B, Cao D, Yu D, Tao D, Hu J et al (2015) Absence of DAB2IP promotes cancer stem cell like signatures and indicates poor survival outcome in colorectal cancer. Sci Rep 5:16578

    Article  PubMed  PubMed Central  Google Scholar 

  14. Nagarsheth N, Wicha MS, Zou WP (2017) Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol 17:559–572

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Niiya M, Niiya K, Kiguchi T, Shibakura M, Asaumi N, Shinagawa K, Ishimaru F, Kiura K, Ikeda K, Ueoka H, Tanimoto M (2003) Induction of TNF-alpha, uPA, IL-8 and MCP-1 by doxorubicin in human lung carcinoma cells. Cancer Chemother Pharmacol 52:391–398

    Article  PubMed  Google Scholar 

  16. Ning Y, Manegold PC, Hong YK, Zhang W, Pohl A, Lurje G, Winder T, Yang D, LaBonte MJ, Wilson PM et al (2011) Interleukin-8 is associated with proliferation, migration, angiogenesis and chemosensitivity in vitro and in vivo in colon cancer cell line models. Int J Cancer 128:2038–2049

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Orditura M, De Vita F, Catalano G, Infusino S, Lieto E, Martinelli E, Morgillo F, Castellano P, Pignatelli C, Galizia G (2002) Elevated serum levels of interleukin-8 in advanced non-small cell lung cancer patients: relationship with prognosis. J Interferon Cytokine Res 22:1129–1135

    Article  PubMed  CAS  Google Scholar 

  18. Park SY, Han J, Kim JB, Yang MG, Kim YJ, Lim HJ, An SY, Kim JH (2014) Interleukin-8 is related to poor chemotherapeutic response and tumourigenicity in hepatocellular carcinoma. Eur J Cancer 50:341–350

    Article  PubMed  CAS  Google Scholar 

  19. Qu J, Zhao L, Zhang PZ, Wang J, Xu N, Mi WJ, Jiang XW, Zhang CM, Qu J (2015) MicroRNA-195 chemosensitizes colon cancer cells to the chemotherapeutic drug doxorubicin by targeting the first binding site of BCL2L2 mRNA. J Cell Physiol 230:535–545

    Article  PubMed  CAS  Google Scholar 

  20. Rial NS, Lazennec G, Prasad AR, Krouse RS, Lance P, Gerner EW (2009) Regulation of deoxycholate induction of CXCL8 by the adenomatous polyposis coli gene in colorectal cancer. Int J Cancer 124:2270–2280

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Schneikert J, Grohmann A, Behrens J (2007) Truncated APC regulates the transcriptional activity of beta-catenin in a cell cycle dependent manner. Hum Mol Genet 16:199–209

    Article  PubMed  CAS  Google Scholar 

  22. Scotto KW (2003) Transcriptional regulation of ABC drug transporters. Oncogene 22:7496–7511

    Article  PubMed  CAS  Google Scholar 

  23. Shao N, Chen LH, Ye RY, Lin Y, Wang SM (2013) The depletion of interleukin-8 causes cell cycle arrest and increases the efficacy of docetaxel in breast cancer cells. Biochem Biophys Res Commun 431:535–541

    Article  PubMed  CAS  Google Scholar 

  24. Shi Z, Yang WM, Chen LP, Yang DH, Zhou Q, Zhu J, Chen JJ, Huang RC, Chen ZS, Huang RP (2012) Enhanced chemosensitization in multidrug-resistant human breast cancer cells by inhibition of IL-6 and IL-8 production. Breast Cancer Res Treat 135:737–747

    Article  PubMed  CAS  Google Scholar 

  25. Sui H, Fan ZZ, Li Q (2012) Signal transduction pathways and transcriptional mechanisms of ABCB1/Pgp-mediated multiple drug resistance in human cancer cells. J Int Med Res 40:426–435

    Article  PubMed  CAS  Google Scholar 

  26. VanKlompenberg MK, Bedalov CO, Soto KF, Prosperi JR (2015) APC selectively mediates response to chemotherapeutic agents in breast cancer. BMC Cancer 15:457

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. VanKlompenberg MK, Leyden E, Arnason AH, Zhang JT, Stefanski CD, Prosperi JR (2017) APC loss in breast cancer leads to doxorubicin resistance via STAT3 activation. Oncotarget 8:102868–102879

    Article  PubMed  PubMed Central  Google Scholar 

  28. Wang Y, Qu Y, Niu XL, Sun WJ, Zhang XL, Li LZ (2011) Autocrine production of interleukin-8 confers cisplatin and paclitaxel resistance in ovarian cancer cells. Cytokine 56:365–375

    Article  PubMed  CAS  Google Scholar 

  29. Waugh DJ, Wilson C (2008) The interleukin-8 pathway in cancer. Clin Cancer Res 14:6735–6741

    Article  PubMed  CAS  Google Scholar 

  30. Wu JT, Kral JG (2005) The NF-kappaB/IkappaB signaling system: a molecular target in breast cancer therapy. J Surg Res 123:158–169

    Article  PubMed  CAS  Google Scholar 

  31. Wu YM, Chen ZJ, Liu H, Wei WD, Lu LL, Yang XL, Liang WT, Liu T, Liu HL, Du J, Wang HS (2015) Inhibition of ERRalpha suppresses epithelial mesenchymal transition of triple negative breast cancer cells by directly targeting fibronectin. Oncotarget 6:25588–25601

    PubMed  PubMed Central  Google Scholar 

  32. Xi G, Hayes E, Lewis R, Ichi S, Mania-Farnell B, Shim K, Takao T, Allender E, Mayanil CS, Tomita T (2016) CD133 and DNA-PK regulate MDR1 via the PI3K- or Akt-NF-kappaB pathway in multidrug-resistant glioblastoma cells in vitro. Oncogene 35:241–250

    Article  PubMed  CAS  Google Scholar 

  33. Yu M, Ocana A, Tannock IF (2013) Reversal of ATP-binding cassette drug transporter activity to modulate chemoresistance: why has it failed to provide clinical benefit? Cancer Metastasis Rev 32:211–227

    Article  PubMed  CAS  Google Scholar 

  34. Zhang ZP, Wang Y, Xu SH, Yu YN, Hussain A, Shen YY, Guo SR (2017) Photothermal gold nanocages filled with temperature sensitive tetradecanol and encapsulated with glutathione responsive polycurcumin for controlled DOX delivery to maximize anti-MDR tumor effects. J Mater Chem B 5:5464–5472

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by the Natural Science Foundation of Zhejiang Province (No. LQ17H160016) and the Zhejiang Provincial Medical and Healthy Science and Technology Projects (No. 2015KYA029).

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Zhejiang Provincial People’s Hospital, 158# Shangtang Rd, Hangzhou, Zhejiang Province, 310014, People’s Republic of China

    Jing Du, Peng Li, Weiquan Wu, Youwei Chen & Hongjun Ruan

  2. People’s Hospital of Hangzhou Medical College, Hangzhou, 310014, People’s Republic of China

    Jing Du, Peng Li, Weiquan Wu, Youwei Chen & Hongjun Ruan

  3. Department of Laboratory Animal Science, Nanchang University, Nanchang, 330006, People’s Republic of China

    Yuanqiao He

  4. Department of Gastroenterology, Central Hospital of Haining, Haining, 314499, People’s Republic of China

    Hongjun Ruan

Authors
  1. Jing Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuanqiao He
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Weiquan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Youwei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hongjun Ruan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hongjun Ruan.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Du, J., He, Y., Li, P. et al. IL-8 regulates the doxorubicin resistance of colorectal cancer cells via modulation of multidrug resistance 1 (MDR1). Cancer Chemother Pharmacol 81, 1111–1119 (2018). https://doi.org/10.1007/s00280-018-3584-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-018-3584-x

Keywords

Search

Navigation