Interleukin-6 differentially regulates androgen receptor transactivation via PI3K-Akt, STAT3, and MAPK, three distinct signal pathways in prostate cancer cells

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Abstract

The effects of IL-6 on prostate cancer cells are well documented yet remain controversial. Some reports suggested that IL-6 could promote prostate cancer cell growth, while others showed that IL-6 could repress prostate cancer cell growth. Here, we systemically examined various IL-6 signaling pathways in prostate cancer cells and found that IL-6 could go through at least three distinct pathways to modulate the functions of androgen receptor (AR), a key transcriptional factor to control the prostate cancer growth. Our results show that IL-6 can enhance AR transactivation via either the STAT3 or MAPK pathways. In contrast, IL-6 can suppress AR transactivation via the PI3K-Akt pathway. Co-existence of these various signaling pathways may result in either additive or conflicting effects on AR transactivation. Together, our results indicate that the balance of these various pathways may then determine the overall effect of IL-6 on AR transactivation.

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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).

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    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.

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