Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain; Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain; Hospital Universitario Reina Sofía, Madrid, Spain.
Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain; Hospital Universitario Reina Sofía, Madrid, Spain.
J Proteomics. 2019 Feb 20;193:217-229. doi: 10.1016/j.jprot.2018.10.012. Epub 2018 Oct 25.
Galiellalactone (GL) is a fungal metabolite that presents antitumor and antiinflammatory activities in vitro and in vivo. Previous studies have shown that GL targets NF-κB and STAT3 pathways and induces G/M cell cycle arrest in androgen-insensitive prostate cancer cells. In this study, we show that GL-induced cell cycle arrest is independent of the NF-κB and STAT3 pathways in DU145 and PC-3 cells, and also that GL did not affect cell cycling in androgen-sensitive prostate cancer cells such as LNCaP and 22Rv1 cells. In addition, we showed confluence resistance to GL in DU145 cells. Using a SWATH proteomic approach we identified a down-regulation of Nucleolar and spindle associated protein 1 (NUSAP1) under DU145 confluence. Moreover the expression of NUSAP1 in LNCaP cells is low compared to DU145 cells. The inhibition of NUSAP1 by siRNAs induced resistance to GL in DU145 cells, suggesting that NUSAP1 may be a target for GL and could be useful as a biomarker for the responsiveness of the antitumor activity of GL. Altogether, our finding shed light to the potential of GL to be developed as a novel treatment of castration resistance prostate cancer.
裂殖菌酸（GL）是一种真菌代谢产物，具有体外和体内抗肿瘤和抗炎活性。先前的研究表明，GL 靶向 NF-κB 和 STAT3 途径，并诱导去势抵抗性前列腺癌细胞中的 G/M 细胞周期停滞。在这项研究中，我们表明 GL 诱导的细胞周期停滞在 DU145 和 PC-3 细胞中不依赖于 NF-κB 和 STAT3 途径，并且 GL 也不影响雄激素敏感性前列腺癌细胞，如 LNCaP 和 22Rv1 细胞的细胞周期。此外，我们在 DU145 细胞中显示出对 GL 的抗融合能力。使用 SWATH 蛋白质组学方法，我们在 DU145 细胞的融合状态下发现核仁纺锤体相关蛋白 1（NUSAP1）的下调。此外，与 DU145 细胞相比，LNCaP 细胞中 NUSAP1 的表达水平较低。用 siRNAs 抑制 NUSAP1 可诱导 DU145 细胞对 GL 的耐药性，表明 NUSAP1 可能是 GL 的靶点，并可用作 GL 抗肿瘤活性反应性的生物标志物。总之，我们的发现为 GL 作为去势抵抗性前列腺癌的新型治疗方法的开发提供了新的思路。
