Galiellalactone is a novel therapeutic candidate against hormone-refractory prostate cancer expressing activated Stat3
Galiellalactone is a novel therapeutic candidate against hormone-refractory prostate cancer expressing activated Stat3
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DOI：
10.1002/pros.20699
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发表时间：
2008-02-15
期刊：
影响因子：
2.8
通讯作者：
Bjartell, Anders
中科院分区：
文献类型：
--
作者：
Hellsten, Rebecka;Johansson, Martin;Bjartell, Anders
背景信号转导子和转录激活子3（Stat 3）在包括前列腺癌（PCa）在内的几种形式的癌症中具有组成性活性（磷酸化）。Stat 3信号传导可能是癌症治疗的一个有趣靶点，因为该途径的抑制介导了这些细胞的生长抑制和细胞凋亡。在这项研究中，我们研究了在体外和体内的真菌代谢产物galiellalactone，Stat 3的直接抑制剂，对PCa细胞的影响。使用人PCa细胞系DU 145、PC-3和LNCaP。使具有皮下PCa细胞异种移植物的裸鼠每天腹膜内注射大蒜内酯，持续3周。通过Western blot分析、免疫细胞化学和Annexin V染色研究了大蒜内酯对培养的PCa细胞凋亡的诱导作用。通过荧光素酶报告基因测定研究了小没食子内酯对Stat 3信号传导的影响。通过Western blot和实时定量PCR分析研究Stat 3相关蛋白和mRNA的表达。Galiellalactone诱导p-Stat 3阳性PCa细胞（雄激素不敏感的DU 145和PC-3）的凋亡，但不诱导缺乏p-Stat 3的细胞（雄激素敏感的LNCaP）的凋亡。Galiellalactone抑制Stat 3介导的荧光素酶活性（IC 50类似于5 μ M），并减少Bcl-2，Bcl-X-L，c-myc和细胞周期蛋白D1的表达。此外，大蒜内酯还能显著抑制DU 145移植瘤的生长（42%，P < 0.002），并降低Bcl-X-L和Mcl-1 mRNA的相对表达。Galiellalactone诱导雄激素不敏感PCa细胞表达p-Stat 3的生长抑制和凋亡。我们认为，galiellalactone是一个潜在的抗肿瘤铅对难治性前列腺癌与组成型活性Stat 3。
BACKGROUND. Signal transducer and activator of transcription 3 (Stat3) is constitutively active (phosphorylated) in several forms of cancer, including prostate cancer (PCa). Stat3 signaling may be an interesting target for cancer therapy since inhibition of this pathway mediates growth inhibition and apoptosis of these cells. In this study we investigated the in vitro and in vivo effects of the fungal metabolite galiellalactone, a direct inhibitor of Stat3, on PCa cells.METHODS. The human PCa cell lines DU145, PC-3, and LNCaP were used. Nude mice with subcutaneous PCa cell xenografts were subjected to daily intraperitoneal injections of galiellalactone for 3 weeks. The effect of galiellalactone on the induction of apoptosis of cultured PCa cells was investigated by Western blot analysis, immunocytochemistry, and annexin V staining. Effects of galiellalactone on Stat3 signaling were investigated by a luciferase reporter gene assay. Expression of Stat3 associated proteins and mRNA was investigated by Western blot and real-time quantitative PCR analysis.RESULTS. Galiellalactone induced apoptosis of p-Stat3 positive PCa cells (androgen-insensitive DU145 and PC-3) but not in cells lacking p-Stat3 (androgen-sensitive LNCaP). Galiellalactone inhibited Stat3-mediated luciferase activity (IC50 similar to 5 mu M) and reduced the expression of Bcl-2, Bcl-X-L, c-myc, and cyclin D1. Furthermore, galiellalactone significantly suppressed DU145 xenograft growth in vivo (42% growth reduction; P < 0.002) and reduced the relative mRNA expression of Bcl-X-L and Mcl-1.CONCLUSIONS. Galiellalactone induced growth inhibition and apoptosis in androgen-insensitive PCa cells expressing p-Stat3. We suggest that galiellalactone is a potential anti-tumor lead against hormone-refractory PCa with constitutively active Stat3.