PO.ET07.02 · 实验与分子治疗
药理学抑制SREBP驱动的脂质生成可抑制前列腺癌的转移进展
Pharmacologic inhibition of SREBP-driven lipogenesis suppresses metastatic progression in prostate cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
前列腺癌（PCa）进展日益被认为是一个由代谢驱动的过程，尤其是通过脂质代谢的改变。固醇调节元件结合蛋白（SREBPs）是调控参与脂质生成基因的主要转录因子，在晚期前列腺癌中常常上调，导致异常脂质积累，并与不良预后和疾病进展相关。尽管在表征前列腺癌的代谢表型方面已取得进展，但在理解SREBP驱动的脂质重塑如何从机制上促进前列腺癌转移播散方面仍存在关键空白。我们对公开可用患者数据集的分析显示，与正常前列腺组织相比，前列腺肿瘤中SREBPs的基因表达升高。此外，我们观察到与原发肿瘤相比，转移样本中SREBP基因表达显著更高。我们还发现，侵袭性更强的PC3M和C4-2B细胞系中SREBPs水平明显高于其侵袭性较弱的对应细胞系PC3和LNCaP。基于这些发现，我们假设通过fatostatin抑制SREBPs可能是对抗致死性转移性前列腺癌的有效治疗策略。我们发现fatostatin抑制侵袭性更强的前列腺癌细胞系的活力、增殖、克隆形成存活、迁移和侵袭，其效力显著高于侵袭性较弱的细胞系。免疫印迹证实，fatostatin在侵袭性更强的前列腺癌细胞系中对SREBPs及其下游靶标的抑制比在侵袭性较弱的细胞系中更为有效。随后我们对所有经fatostatin处理的细胞系进行了RNA-Seq和通路分析。我们发现，与侵袭性较弱的对应细胞系相比，侵袭性更强的前列腺癌细胞系中与EMT和mTORC1相关的通路显著下调。总体而言，我们的结果表明SREBP驱动的脂质代谢从机制上促进前列腺癌侵袭性，药理学抑制SREBPs可能改善致死性转移性前列腺癌的结局。
查看英文原文 English abstract
Prostate cancer (PCa) progression is increasingly recognized as a metabolically driven process, particularly through alterations in lipid metabolism. Sterol regulatory element-binding proteins (SREBPs) are master transcription factors that regulate genes involved in lipogenesis and are often upregulated in advanced prostate cancer, leading to aberrant lipid accumulation, and are associated with poor prognosis and disease progression. Despite advances in characterizing the metabolic phenotype of PCa, a critical gap remains in understanding how SREBP-driven lipid remodeling mechanistically contributes to the metastatic dissemination of PCa. Our analysis of publicly available patient datasets revealed increased gene expression of SREBPs in prostate tumors compared to normal prostate tissue. Furthermore, we observed substantially higher SREBP gene expression in metastatic samples compared to primary tumors. We also found notably higher levels of SREBPs in the more invasive PC3M and C4-2B cell lines than in their less invasive counterparts, PC3 and LNCaP. Based on these findings, we hypothesize that inhibition of SREBPs by fatostatin could be an effective therapeutic strategy against lethal metastatic prostate cancer. We found that fatostatin inhibited the viability, proliferation, clonogenic survival, migration, and invasion of the more invasive PCa cell lines, with significantly greater potency than in less invasive lines. Immunoblotting confirmed that fatostatin inhibited both SREBPs and their downstream targets more effectively in more invasive PCa cell lines than in less invasive ones. We then performed RNA-Seq and pathway analysis on all cell lines treated with fatostatin. We found that pathways related to EMT and mTORC1 are significantly downregulated in the more invasive prostate cancer cell lines compared to their less invasive counterparts. Overall, our results demonstrate that SREBP-driven lipid metabolism mechanistically contributes to PCa invasiveness and pharmacological inhibition of SREBPs may improve outcomes in lethal metastatic prostate cancer.
利益披露 Disclosure
P. R. Parupathi, None.