©2007 LANDES BIOSCIENCE. DO NOT DISTRIBUTE.
Reciprocal Regulation of 5α-Dihydrotestosterone, Interleukin-6
and Interleukin-8 During Proliferation of Epithelial Ovarian Carcinoma
Li Jie Dong1
1Department of Immunology; Tianjin Medical University; Tianjin, P.R. China
2Department of Immunology; Medical College of Chinese People’s Armed Police
Forces; Tianjin, P.R. China
3Department of Oncology; Tianjin Central Maternity Hospital; Tianjin, P.R. China
*Correspondence to: Zhi Yao; Department of Immunology; Tianjin Medical
University; Heping District Qixiangtai Road No.22; Tianjin 300070, P.R. China;
Tel.:+86.22.23542817; Fax:+86.22.23542538; Email: email@example.com/
Yue Wang; Department of Immunology; Medical College of Chinese People’s
Armed Police Forces; Tianjin, P.R. China; Email: firstname.lastname@example.org
Original manuscript submitted: 08/14/06
Revised manuscript(s) submitted: 12/06/06; 02/15/07
Manuscript accepted: 03/01/07
Previously published online as a Cancer Biology & Therapy E-publication:
Natural? Science? Foundation? of? China?
Androgens have been associated with the risk for epithelial ovarian cancer (OVCA).
Both IL-6 and IL-8 are also likely involved in the progression of OVCA. In order to discover
the underline molecular mechanism, we investigated the modulation of androgen and two
cytokines in the growth of epithelial OVCA. In these studies, the effect of 5α-dihydrotes-
tosterone (DHT) on the expression levels of IL-6 and IL-8 was investigated. The effect of
IL-6 and IL-8 on cell growth and androgen receptor (AR) expression was also analyzed.
Gene expression profile analysis revealed that SKOV-3 cells, which express AR, IL-6 and
IL-8 receptors, are suitable model for this study. We found that IL-6 and IL-8 markedly
promoted SKOV-3 cell proliferation. Furthermore, DHT enhanced IL-6 and IL-8 secretion.
Flutamide (Flu), an AR antagonist, completely abolished DHT-stimulated cell growth and
the expression of IL-6 and IL-8. IL-6- or IL-8-induced cell proliferation was completely
blocked by their specific neutralizing antibodies, which partially inhibited DHT-induced
cell growth. In the absence of androgen, both cytokines enhanced AR expression and
AR promoter activation, which was completely blocked by Flu. However, Flu failed to
reduce IL-6-/IL-8-induced cell growth. Pretreatment of SKOV-3 cells with p38 MAPK,
MEK1/2, and ErbB2 MAPK inhibitors, respectively, blocked IL-6-mediated enhancement
of AR transcription while Src inhibitor blocked IL-8 induced AR transcription. These results
provide a novel mechanism that androgens, IL-6 and IL-8 may form a common amplifying
signaling cascade to modulate OVCA growth. Androgen-induced OVCA proliferation
is partially occurring via enhanced IL-6 and IL-8 expression, and IL-6/IL-8 could also
promote OVCA growth by activation of AR gene promoter.
Interleukin-6? (IL-6)? is? a? pleiotropic? cytokine? that? plays? an? important? role? in? cell? ?
involved? in? malignant? transformation? and? progression? of? various? cancers,? including?
©2007 LANDES BIOSCIENCE. DO NOT DISTRIBUTE.
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