Interleukin-6 induces VEGF secretion from prostate cancer cells in a manner independent of androgen receptor activation
Interleukin-6 induces VEGF secretion from prostate cancer cells in a manner independent of androgen receptor activation
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Interleukin-6 以不依赖于雄激素受体激活的方式诱导前列腺癌细胞分泌 VEGF
DOI：
10.1002/pros.23643
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Sugimura Yoshiki
中科院分区：
文献类型：
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作者：
Ishii Kenichiro;Sasaki Takeshi;Iguchi Kazuhiro;Kajiwara Shinya;Kato Manabu;Kanda Hideki;Hirokawa Yoshifumi;Arima Kiminobu;Mizokami Atsushi;Sugimura Yoshiki
前列腺癌（PCa）细胞雄激素敏感性降低是一个重要的临床进展，因为它与细胞进展为去势抵抗性前列腺癌（CRPC）有关。在雄激素剥夺治疗（ADT）期间，基质源性生长因子和细胞因子可激活雄激素受体（AR）。例如，IL-6是一种多功能细胞因子，通过AR激活参与PCa细胞的恶性肿瘤。在本研究中，我们使用雄激素敏感的人前列腺癌细胞系（LNCaP）及其亚系，研究前列腺癌细胞对IL-6处理的反应性与细胞AR信号通路之间的关系。相比之下，雄激素不敏感的AIDL细胞通过在激素耗尽条件下连续传代从LNCaP细胞建立。原始癌相关成纤维细胞（CAFs）PCaSC-8和PCaSC-9细胞分离自PCa patients.ResultsIn成纤维细胞来源于PCa患者，IL-6分泌通常高于正常成纤维细胞。相反，在LNCaP及其亚系中未检测到IL-6分泌。在PCa细胞中检测到可溶性IL-6受体，但在成纤维细胞中未检测到。IL-6处理抑制LNCaP、F10和E9细胞的细胞生长，但不抑制AIDL细胞，并且伴随神经内分泌样分化。在IL-6处理的LNCaP和F10细胞中观察到PSA分泌的诱导。在IL-6处理的LNCaP和AIDL细胞中强烈诱导VEGF分泌。IL-6诱导的VEGF分泌被PI3K抑制剂（LY294002）显著抑制，并且伴随Akt.ConclusionsOur结果表明IL-6可能以独立于AR激活的方式诱导PCa细胞VEGF分泌。为了防止IL-6诱导的VEGF分泌，抑制PI3K/AKT信号通路可能是一个重要的药理学目标，无论ADT如何。
BackgroundThe 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.MethodsThe 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.ResultsIn 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.ConclusionsOur 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.