Interleukin-6 differentially regulates androgen receptor transactivation via PI3K-Akt, STAT3, and MAPK, three distinct signal pathways in prostate cancer cells
Section snippets
Materials and methods
Materials. pCDNA3-cAkt (a constitutively active Akt with a deletion at amino acids 4–129 replaced with a consensus myristylation domain) and pCDNA3-dAkt (a kinase deficient mutant, K179A) were from Dr. Robert Freeman [25]. pSG513-STAT3 and pSG513-STAT3β (a dominant-negative STAT3 with a point mutation) were from Dr. Rolf P. de Groot [26]. LY294002, U0126, and PD98059 were from Calbiochem and DHT was from Sigma. pCMV-AR, pSG5-AR, MMTV-luciferase (MMTV-luc) promoter, and a reporter containing 4
IL-6 differentially induces AR transactivation in various prostate cancer cells
We first investigated the effect of IL-6 on AR transcriptional activity in LNCaP cells by transient transfection with the MMTV-luc reporter plasmid. The region of the MMTV promoter that contains the AREs is required for androgen induction. As shown in Fig. 1A, IL-6 had minimal effect on MMTV-luc activity in the absence of DHT in the LNCaP cells. We then treated the LNCaP cells with a low concentration of DHT (0.1 nM) and a maximum induction (45-fold) of MMTV-luc reporter activity was obtained
Discussion
The role of cytokines in normal prostate biology and prostate cancer is still an emerging area of investigation. IL-6 is significantly elevated in many men with advanced hormone-independent prostate cancer and elevated IL-6 levels may constitute an independent prognostic marker for decreased survival [5]. Thus, it has been predicted that IL-6 signaling plays an important role in androgen-independent progression. IL-6 receptor is expressed in both prostate cancer tissues and prostate cancer cell
Acknowledgments
We are grateful to Drs. R. Freeman and Rolf P. de Groot for their reagents. We thank Karen L. Wolf for helpful reading of the manuscript. We also thank the members in Dr. Chang’s laboratory for technical support and insightful discussion. The work was supported by NIH Grants (DK60905 and DK60948).
References (31)
- et al.
Interleukin 6 receptor mRNA in prostate carcinomas and benign prostate hyperplasia
J. Urol.
(1994) - et al.
Interleukin-6: a candidate mediator of human prostate cancer morbidity
Urology
(1995) - et al.
Interleukin-6 induces G1 arrest through induction of p27(Kip1), a cyclin-dependent kinase inhibitor, and neuron-like morphology in LNCaP prostate tumor cells
Biochem. Biophys. Res. Commun.
(1999) - et al.
Cloning and characterization of human prostate coactivator ARA54, a novel protein that associates with the androgen receptor
J. Biol. Chem.
(1999) - et al.
Cloning and characterization of androgen receptor coactivator, ARA55, in human prostate
J. Biol. Chem.
(1999) - et al.
Activation of the androgen receptor N-terminal domain by interleukin-6 via MAPK and STAT3 signal transduction pathways
J. Biol. Chem.
(2002) - et al.
STAT3β, a splice variant of transcription factor STAT3, is a dominant negative regulator of transcription
J. Biol. Chem.
(1996) - et al.
Phosphatidylinositol-3 kinase is necessary for 12-O-tetradecanoylphorbol-13-acetate-induced cell transformation and activated protein 1 activation
J. Biol. Chem.
(1997) - et al.
Interleukin-6 is an autocrine growth factor in human prostate cancer
Am. J. Pathol.
(2001) - et al.
Characterization of the role of IL-6 in the progression of prostate cancer
Prostate
(1999)
Interleukin-6 and epidermal growth factor promote anchorage-independent growth of immortalized human prostatic epithelial cells treated with N-methyl-N-nitrosourea
Prostate
Circulating levels of interleukin-6 in patients with hormone refractory prostate cancer
Prostate
Interleukin-6 regulates prostate-specific protein expression in prostate carcinoma cells by activation of the androgen receptor
Cancer Res.
Interleukin-6 induces prostate cancer cell growth accompanied by activation of stat3 signaling pathway
Prostate
Requirement of ErbB2 for signalling by interleukin-6 in prostate carcinoma cells
Nature
Cited by (0)
Abbreviations: AR, androgen receptor; PI3K, phosphatidylinositol 3(OH)-kinase; IL6, interleukin 6; wtAR, wild-type AR; DHT, 5α-dihydrotestosterone; MMTV, mouse mammary tumor virus; PSA, prostate specific antigen; luc, luciferase.
- 1
Authors contributed equally to this work.