Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ASCO Annual Meeting 2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

2024 ASCO Annual Meeting

Keep up to date with all the top stories and latest evidence with our hub page, including official congress videos and expert takeaways.
ADVANCED SEARCH
Log in
Top
Radiation Oncology
Published in: Radiation Oncology 1/2013

Open Access 01-12-2013 | Research

The role of IL-6 in the radiation response of prostate cancer

Authors: Chun-Te Wu, Miao-Fen Chen, Wen-Cheng Chen, Ching-Chuan Hsieh

Published in: Radiation Oncology | Issue 1/2013

Login to get access

Abstract

Background

Hormone-resistant (HR) prostate cancers are highly aggressive and respond poorly to treatment. IL-6/STAT3 signaling has been identified to link with the transition of HR and aggressive tumor behavior. The role of IL-6 in the radiation response of prostate cancer was investigated in the present study.

Material and methods

The murine prostate cancer cell line (TRAMP-C1) and the hormone-resistant cell sub-line, TRAMP-HR, were used to assess the radiation response using in vitro clonogenic assays and tumor growth delay in vivo. Biological changes following irradiation were investigated by means of experimental manipulation of IL-6 signaling. Correlations among IL-6 levels, tumor regrowth, angiogenesis and myeloid-derived suppressor cell (MDSC) recruitment were examined in an animal model.

Results

HR prostate cancer cells had a higher expression of IL-6 and more activated STAT3, compared to TRAMP-C1 cells. HR prostate cancer cells had a greater capacity to scavenge reactive oxygen species, suffered less apoptosis, and subsequently were more likely to survive after irradiation. Moreover, IL-6 expression was positively linked to irradiation and radiation resistance. IL-6 inhibition enhanced the radiation sensitivity of prostate cancer, which was associated with increased p53, RT-induced ROS and oxidative DNA damage. Furthermore, when mice were irradiated with a sub-lethal dose, inhibition of IL-6 protein expression attenuated angiogenesis, MDSC recruitment, and decreased tumor regrowth.

Conclusion

These data demonstrate that IL-6 is important in the biological sequelae following irradiation. Therefore, treatment with concurrent IL-6 inhibition is a potential therapeutic strategy for increasing the radiation response of prostate cancer.
Appendix
Available only for authorised users
Literature
1.
Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, Sawyers CL: Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004, 10: 33-39. 10.1038/nm972CrossRefPubMed
2.
Kinkade CW, Castillo-Martin M, Puzio-Kuter A, et al.: Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model. J Clin Invest 2008, 118: 3051-3064.PubMedPubMedCentral
3.
Bernier J, Hall EJ, Giaccia A: Radiation oncology: a century of achievements. Nat Rev Cancer 2004,4(9):737-747.CrossRefPubMed
4.
Rodemann HP, Blaese MA: Responses of normal cells to ionizing radiation. Semin Radiat Oncol 2007,17(2):81-88. 10.1016/j.semradonc.2006.11.005CrossRefPubMed
5.
6.
Deorukhkar A, Krishnan S: Targeting inflammatory pathways for tumor radiosensitization. Biochem Pharmacol 2010,80(12):1904-1914. 10.1016/j.bcp.2010.06.039CrossRefPubMedPubMedCentral
7.
Kishimoto T: Interleukin-6: from basic science to medicine–40 years in immunology. Annu Rev Immunol 2005, 23: 1-21. 10.1146/annurev.immunol.23.021704.115806CrossRefPubMed
8.
Malinowska K, Neuwirt H, Cavarretta IT, et al.: Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor. Endocr Relat Cancer 2009, 16: 155-169.CrossRefPubMed
9.
Bonner JA, Trummell HQ, Willey CD, Plants BA, Raisch KP: Inhibition of STAT-3 results in radiosensitization of human squamous cell carcinoma. Radiother Oncol 2009,92(3):339-344. 10.1016/j.radonc.2009.06.022CrossRefPubMed
10.
Hong DS, Angelo LS, Kurzrock R: Interleukin-6 and its receptor in cancer: implications for translational therapeutics. Cancer 2007,110(9):1911-1928. 10.1002/cncr.22999CrossRefPubMed
11.
12.
13.
Guo Y, Xu F, Lu T, Duan Z, Zhang Z: Interleukin-6 signaling pathway in targeted therapy for cancer. Cancer Treat Rev 2012,38(7):904-910. 10.1016/j.ctrv.2012.04.007CrossRefPubMed
14.
Plante M, Rubin SC, Wong GY, Federici MG, Finstad CL, Gastl GA: Interleukin-6 level in serum and ascites as a prognostic factor in patients with epithelial ovarian cancer. Cancer 1994,73(7):1882-1888. 10.1002/1097-0142(19940401)73:7<1882::AID-CNCR2820730718>3.0.CO;2-RCrossRefPubMed
15.
Zhang GJ, Adachi I: Serum interleukin-6 levels correlate to tumor progression and prognosis in metastatic breast carcinoma. Anticancer Res 1999,19(2B):1427-1432.PubMed
16.
Chen MF, Chen PT, Lu MS, Lin PY, Chen WC, Lee KD: IL-6 expression predicts treatment response and outcome in squamous cell carcinoma of the esophagus. Mol Cancer 2013,12(1):26. 10.1186/1476-4598-12-26CrossRefPubMedPubMedCentral
17.
18.
Kozin SV, Kamoun WS, Huang Y, Dawson MR, Jain RK, Duda DG: Recruitment of myeloid but not endothelial precursor cells facilitates tumor regrowth after local irradiation. Cancer Res 2010,70(14):5679-5685. 10.1158/0008-5472.CAN-09-4446CrossRefPubMedPubMedCentral
19.
Wu CT, Hsieh CC, Lin CC, Chen WC, Hong JH, Chen MF: Significance of IL-6 in the transition of hormone-resistant prostate cancer and the induction of myeloid-derived suppressor cells. J Mol Med (Berl) 2012,90(11):1343-1355. 10.1007/s00109-012-0916-xCrossRef
20.
Chen MF, Chen WC, Chang YJ, Wu CF, Wu CT: Role of DNA methyltransferase 1 in hormone-resistant prostate cancer. J Mol Med (Berl) 2010,88(9):953-962. 10.1007/s00109-010-0640-3CrossRef
21.
Wu CT, Chen WC, Liao SK, Hsu CL, Lee KD, Chen MF: The radiation response of hormone-resistant prostate cancer induced by long-term hormone therapy. Endocr Relat Cancer 2007,14(3):633-643. 10.1677/ERC-07-0073CrossRefPubMed
22.
Chen MF, Hsieh CC, Chen WC, Lai CH: Role of interleukin-6 in the radiation response of liver tumors. Int J Radiat Oncol Biol Phys 2012,84(5):e621-e630. 10.1016/j.ijrobp.2012.07.2360CrossRefPubMed
23.
24.
Li H, Han Y, Guo Q, Zhang M, Cao X: Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-beta 1. J Immunol 2009,182(1):240-249.CrossRefPubMed
25.
Myhre O, Andersen JM, Aarnes H, Fonnum F: Evaluation of the probes 2’,7’-dichlorofluorescin diacetate, luminol, and lucigenin as indicators of reactive species formation. Biochem Pharmacol 2003,65(10):1575-1582. 10.1016/S0006-2952(03)00083-2CrossRefPubMed
26.
Sharma S, Sharma MC, Sarkar C: Morphology of angiogenesis in human cancer: a conceptual overview, histoprognostic perspective and significance of neoangiogenesis. Histopathology 2005,46(5):481-489. 10.1111/j.1365-2559.2005.02142.xCrossRefPubMed
27.
Tulard A, Hoffschir F, de Boisferon FH, Luccioni C, Bravard A: Persistent oxidative stress after ionizing radiation is involved in inherited radiosensitivity. Free Radic Biol Med 2003,35(1):68-77. 10.1016/S0891-5849(03)00243-0CrossRefPubMed
28.
Wallner L, Dai J, Escara-Wilke J, et al.: Inhibition of interleukin-6 with CNTO328, an anti-interleukin-6 monoclonal antibody, inhibits conversion of androgen-dependent prostate cancer to an androgen-independent phenotype in orchiectomized mice. Cancer Res 2006, 66: 3087-3095. 10.1158/0008-5472.CAN-05-3447CrossRefPubMed
29.
Fizazi K, De Bono JS, Flechon A, et al.: Randomised phase II study of siltuximab (CNTO 328), an anti-IL-6 monoclonal antibody, in combination with mitoxantrone/prednisone versus mitoxantrone/prednisone alone in metastatic castration-resistant prostate cancer. Eur J Cancer 2012, 48: 85-93.CrossRefPubMed
30.
Trikha M, Corringham R, Klein B, Rossi JF: Targeted anti-interleukin-6 monoclonal antibody therapy for cancer: a review of the rationale and clinical evidence. Clin Cancer Res 2003,9(13):4653-4665.PubMedPubMedCentral
31.
Leu CM, Wong FH, Chang C, Huang SF, Hu CP: Interleukin-6 acts as an antiapoptotic factor in human esophageal carcinoma cells through the activation of both STAT3 and mitogen-activated protein kinase pathways. Oncogene 2003,22(49):7809-7818. 10.1038/sj.onc.1207084CrossRefPubMed
32.
Lowndes NF, Murguia JR: Sensing and responding to DNA damage. Curr Opin Genet Dev 2000,10(1):17-25. 10.1016/S0959-437X(99)00050-7CrossRefPubMed
33.
Achanta G, Huang P: Role of p53 in sensing oxidative DNA damage in response to reactive oxygen species-generating agents. Cancer Res 2004,64(17):6233-6239. 10.1158/0008-5472.CAN-04-0494CrossRefPubMed
34.
Colombel M, Radvanyi F, Blanche M, et al.: Androgen suppressed apoptosis is modified in p53 deficient mice. Oncogene 1999, 10: 1269-1274.
35.
Burchardt M, Burchardt T, Shabsigh A, et al.: Reduction of wild type p53 function confers a hormone resistant phenotype on LNCaP prostate cancer cells. Prostate 2001, 48: 225-230. 10.1002/pros.1101CrossRefPubMed
36.
Niu G, Wright KL, Ma Y, et al.: Role of Stat3 in regulating p53 expression and function. Mol Cell Biol 2005,25(17):7432-7440. 10.1128/MCB.25.17.7432-7440.2005CrossRefPubMedPubMedCentral
37.
Sun Y, Nelson PS: Molecular pathways: involving microenvironment damage responses in cancer therapy resistance. Clin Cancer Res 2012,18(15):4019-4025. 10.1158/1078-0432.CCR-11-0768CrossRefPubMedPubMedCentral
38.
Lee SO, Lou W, Hou M, de Miguel F, Gerber L, Gao AC: Interleukin-6 promotes androgen-independent growth in LNCaP human prostate cancer cells. Clin Cancer Res 2003,9(1):370-376.PubMed
39.
Steiner H, Berger AP, Godoy-Tundidor S, et al.: An autocrine loop for vascular endothelial growth factor is established in prostate cancer cells generated after prolonged treatment with interleukin 6. Eur J Cancer 2004,40(7):1066-1072. 10.1016/j.ejca.2003.11.033CrossRefPubMed
40.
Yang L, DeBusk LM, Fukuda K, et al.: Expansion of myeloid immune suppressor Gr + CD11b + cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell 2004,6(4):409-421. 10.1016/j.ccr.2004.08.031CrossRefPubMed
Metadata
Title
The role of IL-6 in the radiation response of prostate cancer
Authors
Chun-Te Wu
Miao-Fen Chen
Wen-Cheng Chen
Ching-Chuan Hsieh
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Radiation Oncology / Issue 1/2013
Electronic ISSN: 1748-717X
DOI
https://doi.org/10.1186/1748-717X-8-159

Other articles of this Issue 1/2013

Radiation Oncology 1/2013 Go to the issue

Methodology

Standardized treatment planning methodology for passively scattered proton craniospinal irradiation

Research

Dose to organs at risk in the upper abdomen in patients treated with extended fields by helical tomotherapy: a dosimetric and clinical preliminary study

Research

Concurrent whole brain radiotherapy and bortezomib for brain metastasis

Research

CBCT-based volumetric and dosimetric variation evaluation of volumetric modulated arc radiotherapy in the treatment of nasopharyngeal cancer patients

Research

Impact of very long time output variation in the treatment of total marrow irradiation with helical tomotherapy

Research

Is adjuvant radiotherapy warranted in resected pT1-2 node-positive rectal cancer?