Singh P Raja, Priya E Sugantha, Balakrishnan S, Arunkumar R, Sharmila G, Rajalakshmi M, Arunakaran J
Department of Endocrinology, Dr. ALM. Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, 600 113, India.
PG & Research Department of Biotechnology & Bioinformatics, Holy Cross College, Tiruchirapalli, 620 002, India.
Biomed Pharmacother. 2016 Dec;84:1623-1634. doi: 10.1016/j.biopha.2016.10.076. Epub 2016 Nov 23.
Prostate cancer is the most prominent cancer in men, experiencing a relapse in disease often express high serum TNF-α levels. It has been correlated with increased cell survival and proliferation of prostate cancer cells. Previous studies reported that nimbolide, a terpenoid derived from the leaves and flowers of neem tree inhibits cancer growth through selective modulation of cell signaling pathways linked to inflammation, survival, proliferation, angiogenesis and metastasis.
The present study aimed to examine the effect of nimbolide at 1 and 2μM concentrations on TNF-α/TNFR1 mediated signaling molecules involved in cell survival and proliferation in PC-3 cell line via NF-κB and MAPK pathways by real time PCR and western blot. Protein and compound interaction were performed by Molecular docking analysis.
Our results indicate that nimbolide treatment suppressed expression of TNF-α, SODD, Grb2, SOS mRNA and modulated TNF-α/TNFR1 regulated NF-κB and MAPK signaling molecules in PC-3 cells. Additional molecular dynamics simulation studies confirmed the stability of nimbolide and signaling molecules binding interactions. Binding pose analysis revealed the significance of hydrogen bond interactions for effective stabilization of virtual ligand protein complexes.
Nimbolide inhibited prostate cancer cell survival and proliferation via NF-κB and MAPK pathways.
前列腺癌是男性中最常见的癌症，疾病复发时血清TNF-α水平通常较高。这与前列腺癌细胞的存活和增殖增加有关。先前的研究报道，印楝素是一种从印楝树叶和花中提取的萜类化合物，通过选择性调节与炎症、存活、增殖、血管生成和转移相关的细胞信号通路来抑制癌症生长。
本研究旨在通过实时PCR和蛋白质印迹法，检测1μM和2μM浓度的印楝素对PC-3细胞系中通过NF-κB和MAPK途径参与细胞存活和增殖的TNF-α/TNFR1介导的信号分子的影响。通过分子对接分析进行蛋白质与化合物的相互作用研究。
我们的结果表明，印楝素处理可抑制PC-3细胞中TNF-α、SODD、Grb2、SOS mRNA的表达，并调节TNF-α/TNFR1调节的NF-κB和MAPK信号分子。额外的分子动力学模拟研究证实了印楝素与信号分子结合相互作用的稳定性。结合姿态分析揭示了氢键相互作用对虚拟配体-蛋白质复合物有效稳定的重要性。
印楝素通过NF-κB和MAPK途径抑制前列腺癌细胞的存活和增殖。
