Reciprocal regulation of 5α-dihydrotestosterone, Interleukin-6 and interleukin-8 during proliferation of epithelial ovarian carcinoma

Abstract

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-dihydrotestosterone (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.