Interleukin‐6 induces VEGF secretion from prostate cancer cells in a manner independent of androgen receptor activation. Issue 11 (29th April 2018)

• Record Type: Journal Article
• Authors: Ishii, Kenichiro; Sasaki, Takeshi; Iguchi, Kazuhiro; Kajiwara, Shinya; Kato, Manabu; Kanda, Hideki; Hirokawa, Yoshifumi; Arima, Kiminobu; Mizokami, Atsushi; Sugimura, Yoshiki
• Is Part Of: Prostate. Volume 78:Issue 11(2018)
• Page Start: 849
• Page End: 856
• Publication Date: 2018-04-29
• Subjects: androgen receptor (AR) activation -- interleukin‐6 (IL‐6) -- PI3K/AKT signaling pathway -- prostate cancer -- VEGF; Prostate -- Diseases -- Periodicals; 616
• DOI: 10.1002/pros.23643
• Languages: English
• ISSNs: 0270-4137

Abstract

Abstract : Background: The reduced androgen‐sensitivity of prostate cancer (PCa) cells is an important clinical development because of its association with the cells' progression to castration‐resistant prostate cancer (CRPC). During androgen deprivation therapy (ADT), stroma‐derived growth factors and cytokines can activate the androgen receptor (AR). For example, IL‐6 is a multifunctional cytokine that is involved in the malignancy of PCa cells through AR activation. In the present study, we used an androgen‐sensitive human PCa cell line (LNCaP) and its sublines to investigate the relationship between the responsiveness of PCa cells to IL‐6 treatment and the cellular AR signaling pathway. Methods: The androgen‐low‐sensitive F10 and E9 cells were obtained from LNCaP cells by limiting dilution method in regular culture condition. In contrast, the androgen‐insensitive AIDL cells were established from LNCaP cells by continuous passaging in hormone‐depleted condition. Original carcinoma‐associated fibroblasts (CAFs) PCaSC‐8 and PCaSC‐9 cells were isolated from needle biopsy samples of PCa patients. Results: In fibroblasts derived from PCa patients, IL‐6 secretion was generally higher than that observed with normal fibroblasts. In contrast, IL‐6 secretion was not detected in LNCaP and its sublines. The soluble IL‐6 receptor was detected in PCa cells but not in fibroblasts. IL‐6 treatment suppressed cell growth of LNCaP, F10, and E9 cells but not AIDL cells and it was accompanied with neuroendocrine‐like differentiation. Induction of PSA secretion was observed in IL‐6‐treated LNCaP and F10 cells. VEGF secretion was strongly induced in IL‐6‐treated LNCaP and AIDL cells. IL‐6‐induced VEGF secretion was significantly suppressed by a PI3K inhibitor (LY294002) and it was accompanied by inhibited phosphorylation of Akt. Conclusions: Our results suggest that IL‐6 might induce VEGF secretion from PCa cells in a manner independent of AR activation. To prevent IL‐6‐induced VEGF secretion, inhibition of the PI3K/AKT signaling pathway could be an important pharmacological goal regardless of ADT.