Hobisch A, Eder I E, Putz T, Horninger W, Bartsch G, Klocker H, Culig Z
Department of Urology, University of Innsbruck, Austria.
Cancer Res. 1998 Oct 15;58(20):4640-5.
Interleukin-6 (IL-6) levels are frequently elevated in sera of patients with metastatic prostate cancer. IL-6 receptors are expressed in prostate cancer cell lines, as well as in benign prostate hyperplasia and prostate cancer tissue specimens. The androgen receptor (AR) is a key transcription factor that is present in all stages of prostate carcinoma, even in therapy-refractory tumors. In an attempt to investigate possible cross-talk between IL-6 and androgen signal transduction cascades, we tested the effects of this cytokine on AR transcriptional activity. The regulation of AR activity by IL-6 was studied in DU-145 cells, which were cotransfected with the androgen-responsive reporter plasmid ARE2TATACAT and the AR expression vector pSG5AR. We show that IL-6 up-regulates AR activity in a ligand-independent manner, as well as synergistically, with very low doses of the synthetic androgen methyltrienolone (5-10 pM). Therefore, AR activation by IL-6 may be operative in prostate cancer patients who have decreased androgen levels because of androgen ablation therapy. The maximal induction of reporter gene activity by IL-6 alone (50 ng/ml) was 67% of that stimulated by 1 nM of methyltrienolone. The nonsteroidal antiandrogen bicalutamide (Casodex) nearly completely inhibited AR activation by IL-6. IL-6 effects on AR activity were also abolished or greatly reduced by inhibitors of protein kinase A and C and mitogen-activated protein kinase pathways. In concordance with the results obtained in DU-145 cells, IL-6 induced AR-regulated prostate-specific antigen mRNA and protein in LNCaP cells. Stimulation of prostate-specific antigen protein secretion by IL-6 was antagonized by bicalutamide and inhibitors of protein kinase A and mitogen-activated protein kinase signaling pathways. Taken together, our data show for the first time that IL-6 is a nonsteroidal activator of the AR and that this activation is implicated in the regulation of prostate-specific proteins. Keeping in mind that IL-6, its receptor, and the AR are expressed in prostate cancers, cross-talk between IL-6 and AR signaling pathways may have clinical significance.
转移性前列腺癌患者血清中的白细胞介素-6（IL-6）水平常常升高。IL-6受体在前列腺癌细胞系以及良性前列腺增生和前列腺癌组织标本中均有表达。雄激素受体（AR）是一种关键转录因子，存在于前列腺癌的各个阶段，即使在治疗难治性肿瘤中也是如此。为了研究IL-6与雄激素信号转导级联之间可能存在的相互作用，我们测试了这种细胞因子对AR转录活性的影响。在DU-145细胞中研究了IL-6对AR活性的调节作用，这些细胞与雄激素反应性报告质粒ARE2TATACAT和AR表达载体pSG5AR共转染。我们发现，IL-6以不依赖配体的方式上调AR活性，并且与极低剂量的合成雄激素甲基三烯醇酮（5 - 10 pM）协同上调。因此，IL-6介导的AR激活可能在因雄激素剥夺疗法导致雄激素水平降低的前列腺癌患者中起作用。单独使用IL-6（50 ng/ml）对报告基因活性的最大诱导作用是1 nM甲基三烯醇酮刺激作用的67%。非甾体类抗雄激素比卡鲁胺（康士得）几乎完全抑制IL-6对AR的激活。蛋白激酶A和C以及丝裂原活化蛋白激酶途径的抑制剂也消除或大大降低了IL-6对AR活性的影响。与在DU-145细胞中获得的结果一致，IL-6在LNCaP细胞中诱导AR调节的前列腺特异性抗原mRNA和蛋白表达。比卡鲁胺以及蛋白激酶A和丝裂原活化蛋白激酶信号通路的抑制剂拮抗了IL-6对前列腺特异性抗原蛋白分泌的刺激作用。综上所述，我们的数据首次表明IL-6是AR的非甾体类激活剂，并且这种激活与前列腺特异性蛋白的调节有关。鉴于IL-6及其受体以及AR在前列腺癌中均有表达，IL-6与AR信号通路之间的相互作用可能具有临床意义。
