Abstract
Aim:
Interleukin-6 (IL-6) is a pleiotropic cytokine that is associated with tumor metastasis and prostate cancer. We evaluated the mechanism and effect of 17-(allylamino)-17-demethoxygeldanamycin (17AAG), a novel inhibitor of heat shock protein 90 (Hsp90), on the IL-6 gene expression in human prostatic carcinoma (PC-3) cells.
Methods:
Quantitative IL-6 and IL-6 receptor (IL-6R) expressions were assessed using RT-PCR. The deregulation of 17AAG and phor-bol 12-myristate 13-acetate (PMA) on the IL-6 gene was determined by ELISA and transient gene expression assays using an IL-6 reporter vector.
Results:
Although the IL-6R is ubiquitously expressed by prostatic epithelium cells, the IL-6 expression is only found in advanced prostatic carcinoma cells, such as PC-3 and DU145. Further studies using RT-PCR indicated that 17AAG downregulated the gene expression of IL-6. ELISA and the transient gene expression assay revealed that 17AAG blocked the stimulation of PMA of IL-6 gene expression in PC-3 cells. The PMA-induced IL-6 gene expression is dependent on the NF-κB response element. However, the effect of 17AAG appears to be mediated via a region located at -149 to +8 bp upstream of the transcriptional starting site of the IL-6 gene, and might not be through the NF-κB signaling pathway.
Conclusion:
The present study reveals that IL-6 is transcriptionally downregulated in human prostatic carcinoma cells in response to 17AAG. This result suggests the presence of a novel Hsp90 mediation pathway that is involved in the deregulation on the transcription of the human IL-6 gene in human prostate cancer.
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References
Royuela M, Ricote M, Parsons MS, Garcia-Tunon I, Paniagua R, De Miguel MR Immunohistochemical analysis of the IL-6 family of cytokines and their receptor in benign, hyperplasic and malignant human prostate. J Pathol 2004; 202: 41–9.
Palmer J, Hertzog PJ, Hammacher A . Differential expression and effects of gpl30 cytokines and receptors in prostate cancer cells. Int J Biochem Cell Biol 2004; 36: 2258–69.
Edwards J, Bartlett JMS . The androgen receptor and signal-transduction pathways in hormone-refractory prostate cancer. Part 2: androgen-receptor cofactors and bypass pathways. BJU Int 2005; 95: 1327–35.
Pfitzenmaier J, Vessella R, Higano CS, Noteboom JL, Wallace D Jr, Corey E . Elevation of cytokine levels in cachectic patients with prostate carcinoma. Cancer 2003; 97: 1211–6.
George DJ, Halabi S, Shepard TF, Sanford B, Vogelzang NJ, Small EJ, et al. The prognostic significance of plasma interleukin-6 levels in patients with metastatic hormone-refractory prostate cancer: results from cancer and leukemia group B 9480. Clin Cancer Res 2005; 11: 1815–20.
Jia L, Choong CS, Ricciardelli C, Kim J, Tilley WD, Coetzee GA . Androgen receptor signaling: mechanism of interleukin-6 inhibition. Cancer Res 2004; 64: 2619–26.
Culig Z, Steiner H, Bartsch G, Hobisch A . Interleukin-6 regulation of prostate cancer cells growth. J Cell Biochem 2005; 95: 497–505.
Ritossa F . Discovery of the heat shock response. Cell Stress Chaperones 1996; 1: 97–8.
Cullinan SB, Whitesell L . Heat shock protein 90: a unique chemo-therapeutic target. Semin Oncol 2006; 33: 457–65.
Lattouf JB, Srinivasan R, Pinto PA, Linehan WM, Neckers L . Mechanisms of disease: the role of heat-shock protein 90 in genitourinary malignancy. Nat Clin Pract Urol 2006; 3: 590–600.
Solit DB, Scher H, Rosen N . Hsp90 as a therapeutic target in prostate cancer. Semin Oncol 2003; 30: 709–16.
Ripley BJM, Isenberg DA, Latchman DS . Elevated levels of the 90 kDa heat shock protein (hsp90) in SLE correlate with levels of IL-6 and autoantibodies to hsp90. J Autoimmun 2001; 17: 341–6.
Cardillo MR, Ippoliti F . IL-6, IL-10 and HSP90 expression in tissue microarrays from human prostate cancer assessed by computer-assisted image analysis. Anticancer Res 2006; 26: 3409–16.
Tsui KH, Hsieh WC, Lin MH, Chang PL, Juang HH . Triiodothyronine modulates cell proliferation of human prostatic carcinoma cells by downregulation of the B-cell translocation gene 2. Prostate 2008; 68: 610–9.
Tsui KH, Chang PL, Juang HH . Manganese antagonizes iron blocking mitochondrial acontiase expresson in human prostate carcinoma cells. Asian JAndrol 2006; 8: 307–16.
Steiner H, Godoy-Tundidor S, Rogatsch H, Berger AP, Fuchs D, Comuzzi B, et al. Accelerated in vivo growth of prostate tumors that up-regulate interleukin-6 is associated with reduced retinoblastoma protein expression and activation of the mitogen-activated protein kinase pathway. Am J Pathol 2003; 162: 655–63.
George DJ, Halabi S, Shepard TF, Sanford B, Vogelzang NJ, Small EJ, et al. The prognostic significance of plasma interleukin-6 levels in patients with metastatic hormone-refractory prostate cancer: results from cancer and leukemia group B 9480. Clin Cancer Res 2005; 11: 1815–20.
Araki S, Omori Y, Lyn D, Singh RK, Meinbach DM, Sandman Y, et al. Interleukin-8 is a molecular determinant of androgen independence and progression in prostate cancer. Cancer Res 2007; 67: 6854–62.
Chung TDK, Yu JJ, Spiotto MT, Bartkowski M, Simons JW . Characterization of the role of IL-6 in the progression of prostate cancer. Prostate 1999; 38: 199–207.
Abdul M, Hoosein N . Differences in the expression and effects of interleukin-1 and 2 on androgen-sensitive and -insensitive human prostate cancer cell lines. Cancer Let 2000; 149: 37–42.
Steiner H, Cavarretta IT, Moser PL, Berger AP, Bektic J, Dietrich H, et al. Regulation of growth of prostate cancer cells selected in the presence of interleukin-6 by the anti-interleukin-6 antibody CNTO326. Prostate 2006; 66: 1744–52.
Harashima K, Akimoto T, Nonaka T, Tsuzuki K, Mitsuhashi N, Nakano T . Heat shock protein (90) chaperon complex inhibitor radiciol, potentiated radiation-induced cell killing in a hormone-sensitive prostate cancer cell line through degradation of androgen receptor. Int J Radiat Biol 2005; 81: 63–76.
Goetz MP, Toft DO, Ames MM, Erlichman C . The Hsp90 chaperone complex as a novel target for cancer therapy. Ann Oncol 2003; 14: 1169–76.
Wax S, Piecyk M, Maritim B, Anderson P . Geldanamycin inhibits the production of inflammatory cytokines inactivated macrophages by reducing the stability and translation of cytokine transcripts. Arthritis Rheum 2003; 48: 541–50.
Xiao W, Hodge DR, Wang L, Yang X, Zhang X, Farrar W . Cooperative function between nuclear factors NF-κB and CCAAT/enhancer-binding protein-β (C/EBP-β) regulate the IL-6 promoter in autocrine human prostate cancer cells. Prostate 2004; 61: 354–70.
Zerbini LF, Wang Y, Cho JY, Libermann TA . Constitutive activation of nuclear factor κB p50/65 and Fra-1 and JunD is essential for deregulated interleukin 6 expression in prostate cancer. Cancer Res 2003; 63: 2206–15.
Keller ET, Chang C, Ershler WB . Inhibiton of NF-κB activity through maintenance of IκBα levels contributes to dihydrotestosterone-mediated repression of the interleukin-6 promoter. J Biol Chem 1996; 271: 26267–75.
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This research was supported by Chang Gung Memory Hospital research grants CMRP-G340663 and CMRP-D160131, and National Science Council (Taiwan) grants 97-2320-B-182-023-MY3 and 96-2314-B-182A-016-MY2.
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Tsui, Kh., Feng, Th., Hsieh, Wc. et al. Expression of interleukin-6 is downregulated by 17-(allylamino)-17-demethoxygeldanamycin in human prostatic carcinoma cells. Acta Pharmacol Sin 29, 1334–1341 (2008). https://doi.org/10.1111/j.1745-7254.2008.00887.x
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DOI: https://doi.org/10.1111/j.1745-7254.2008.00887.x
