文章：

SBFI抑制剂重编程前列腺癌细胞转录组景观诱导细胞死亡

SBFI Inhibitors Reprogram Transcriptomic Landscape of Prostate Cancer Cells Leading to Cell Death

原文发布日期：21 November 2025

DOI: 10.3390/cancers17233723

类型: Article

开放获取: 是

英文摘要：

Background: Prostate cancer (PCa) remains the second leading cause of cancer-related deaths in men in the United States. Fatty acid-binding protein 5 (FABP5), a member of a class of intracellular lipid transporters, promotes PCa progression via enhanced lipid metabolism and trafficking of lipid ligands. Previous work from our group has demonstrated that small-molecule FABP5 inhibitors based on the truxillic-acid monoester scaffold reduce PCa growth. Methods: Here, we assessed the effect of third-generation FABP5 inhibitors on the PCa cell cycle, proliferation, apoptosis, signaling pathway activity, and transcriptomic landscape. Results: We demonstrate that the third-generation FABP5 inhibitor SBFI-1143 significantly inhibits the viability of PCa cells by arresting them at the G0/G1 and G2/M phases of the cell cycle, inducing apoptosis, and promoting cell death. Strikingly, SBFI-1143 efficiently inhibited the growth of PCa spheroids compared to its predecessor, SBFI-103. RNA-seq and Gene Set Enrichment Analysis demonstrated that SBFI-1143 more effectively suppressed pathways involved in cell cycle progression, cell cycle division, and chromosome organization while upregulating genes associated with endoplasmic reticulum stress, responses to incorrectly folded proteins, and regulating apoptosis, compared to SBFI-103. Notably, SBFI-1143 treatment downregulated genes associated with the subpopulation of PCa cells characterized by a lineage plasticity-related signature, related to trans-differentiation, recurrence, and poor cancer prognosis. Conclusions: Our findings demonstrate that SBFI-1143 significantly alters the transcriptomic landscape of prostate cancer and may serve as a potentially effective therapeutic option for this disease.

摘要翻译： 

背景：前列腺癌（PCa）仍是美国男性癌症相关死亡的第二大原因。脂肪酸结合蛋白5（FABP5）作为细胞内脂质转运蛋白家族成员，通过增强脂质代谢及脂质配体运输促进前列腺癌进展。本课题组前期研究表明，基于松香酸单酯骨架的小分子FABP5抑制剂可抑制前列腺癌生长。方法：本研究评估了第三代FABP5抑制剂对前列腺癌细胞周期、增殖、凋亡、信号通路活性及转录组图谱的影响。结果：我们发现第三代FABP5抑制剂SBFI-1143通过阻滞细胞周期于G0/G1期和G2/M期、诱导细胞凋亡及促进细胞死亡，显著抑制前列腺癌细胞活力。值得注意的是，与上一代抑制剂SBFI-103相比，SBFI-1143能更有效地抑制前列腺癌球状体的生长。RNA测序及基因集富集分析显示，相较于SBFI-103，SBFI-1143更显著地抑制细胞周期进程、细胞周期分裂及染色体组织相关通路，同时上调内质网应激、错误折叠蛋白反应及凋亡调控相关基因。尤为重要的是，SBFI-1143处理可下调具有谱系可塑性特征的前列腺癌细胞亚群相关基因，该亚群与转分化、癌症复发及不良预后密切相关。结论：本研究证实SBFI-1143能显著改变前列腺癌的转录组图谱，有望成为该疾病的潜在有效治疗策略。

原文链接：

SBFI Inhibitors Reprogram Transcriptomic Landscape of Prostate Cancer Cells Leading to Cell Death