Department of Physiology, University of Pennsylvania, Philadelphia, PA, USA.
Department of Medicine, Penn State College of Medicine, Hershey, PA, USA.
Sci Rep. 2022 Jan 10;12(1):359. doi: 10.1038/s41598-021-04117-7.
The schweinfurthin family of natural compounds exhibit a unique and potent differential cytotoxicity against a number of cancer cell lines and may reduce tumor growth in vivo. In some cell lines, such as SF-295 glioma cells, schweinfurthins elicit cytotoxicity at nanomolar concentrations. However, other cell lines, like A549 lung cancer cells, are resistant to schweinfurthin treatment up to micromolar concentrations. At this time, the precise mechanism of action and target for these compounds is unknown. Here, we employ RNA sequencing of cells treated with 50 nM schweinfurthin analog TTI-3066 for 6 and 24 h to elucidate potential mechanisms and pathways which may contribute to schweinfurthin sensitivity and resistance. The data was analyzed via an interaction model to observe differential behaviors between sensitive SF-295 and resistant A549 cell lines. We show that metabolic and stress-response pathways were differentially regulated in the sensitive SF-295 cell line as compared with the resistant A549 cell line. In contrast, A549 cell had significant alterations in response genes involved in translation and protein metabolism. Overall, there was a significant interaction effect for translational proteins, RNA metabolism, protein metabolism, and metabolic genes. Members of the Hedgehog pathway were differentially regulated in the resistant A549 cell line at both early and late time points, suggesting a potential mechanism of resistance. Indeed, when cotreated with the Smoothened inhibitor cyclopamine, A549 cells became more sensitive to schweinfurthin treatment. This study therefore identifies a key interplay with the Hedgehog pathway that modulates sensitivity to the schweinfurthin class of compounds.
天然化合物 Schweinfurthin 家族对多种癌细胞系表现出独特而强效的细胞毒性，并且可能减少体内肿瘤生长。在某些细胞系中，如 SF-295 神经胶质瘤细胞，Schweinfurthins 在纳摩尔浓度下就具有细胞毒性。然而，其他细胞系，如 A549 肺癌细胞，对 Schweinfurthin 处理的抗性高达微摩尔浓度。此时，这些化合物的确切作用机制和靶标尚不清楚。在这里，我们采用 RNA 测序研究了用 50 nM Schweinfurthin 类似物 TTI-3066 处理 6 和 24 h 的细胞，以阐明可能导致 Schweinfurthin 敏感性和抗性的潜在机制和途径。通过交互模型分析数据，观察敏感 SF-295 和抗性 A549 细胞系之间的差异行为。我们表明，代谢和应激反应途径在敏感 SF-295 细胞系中与抗性 A549 细胞系相比存在差异调节。相比之下，A549 细胞中与翻译和蛋白质代谢相关的反应基因发生了显着变化。总体而言，翻译蛋白、RNA 代谢、蛋白质代谢和代谢基因存在显着的相互作用效应。Hedgehog 途径的成员在抗性 A549 细胞系中在早期和晚期时间点都存在差异调节，表明存在潜在的抗性机制。事实上，当与 Smoothened 抑制剂 cyclopamine 共同处理时，A549 细胞对 Schweinfurthin 处理变得更加敏感。因此，本研究确定了与 Hedgehog 途径的关键相互作用，该途径调节对 Schweinfurthin 类化合物的敏感性。
