Clostridium butyricum and its metabolite butyrate promote ferroptosis susceptibility in pancreatic ductal adenocarcinoma.

IF 4.9 2区 医学 Q2 CELL BIOLOGY Cellular Oncology Pub Date : 2023-12-01 Epub Date: 2023-06-01 DOI:10.1007/s13402-023-00831-8
Xiaotong Yang, Zhengyan Zhang, Xuqing Shen, Junyi Xu, Yawen Weng, Wei Wang, Jing Xue
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引用次数: 1

Abstract

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with limited therapeutic options. The diversity and composition of the intratumoral microbiota are associated with PDAC outcomes, and modulating the tumor microbiota has the potential to influence tumor growth and the host immune response. Here, we explore whether intervention with butyrate-producing probiotics can limit PDAC progression.

Methods: Based on the TCGA (PAAD) database, we analyzed the differential communities of intratumoral microbiota in PDAC patients with long survival and short survival and explored the relevant mechanisms of Clostridium butyricum and its metabolite butyrate in the treatment of PDAC. Treatment with Clostridium butyricum or butyrate in combination with the ferroptosis inducer RSL3 in a PDAC mouse model has an inhibitory effect on PDAC progression. The potential molecular mechanisms were verified by flow cytometry, RNA-seq, Western blotting, qRT‒PCR and immunofluorescence.

Results: We found that the tumoral butyrate-producing microbiota was linked to a better prognosis and less aggressive features of PDAC. Intervention with Clostridium butyricum or its metabolite butyrate triggered superoxidative stress and intracellular lipid accumulation, which enhanced ferroptosis susceptibility in PDAC.

Conclusion: Our study reveals a novel antitumor mechanism of butyrate and suggests the therapeutic potential of butyrate-producing probiotics in PDAC.

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丁酸梭菌及其代谢物丁酸盐促进胰腺导管腺癌中铁下垂的易感性。
目的:胰腺导管腺癌(PDAC)是一种高度侵袭性的疾病,治疗选择有限。肿瘤内微生物群的多样性和组成与PDAC结果相关,调节肿瘤微生物群有可能影响肿瘤生长和宿主免疫反应。在这里,我们探讨是否干预产生丁酸的益生菌可以限制PDAC的进展。方法:基于TCGA (PAAD)数据库,分析长生存期和短生存期PDAC患者瘤内微生物群落差异,探讨丁酸梭菌及其代谢物丁酸盐在PDAC治疗中的相关机制。在PDAC小鼠模型中,丁酸梭菌或丁酸梭菌联合铁下垂诱导剂RSL3治疗对PDAC进展有抑制作用。通过流式细胞术、RNA-seq、Western blotting、qRT-PCR和免疫荧光等方法验证了其潜在的分子机制。结果:我们发现肿瘤产生丁酸盐的微生物群与PDAC更好的预后和更少的侵袭性特征有关。用丁酸梭菌或其代谢物丁酸盐干预可引发超氧化应激和细胞内脂质积累,从而增强PDAC患者对铁中毒的敏感性。结论:本研究揭示了丁酸酯的一种新的抗肿瘤机制,提示了产丁酸酯益生菌在PDAC中的治疗潜力。
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来源期刊
Cellular Oncology
Cellular Oncology ONCOLOGY-CELL BIOLOGY
CiteScore
10.30
自引率
1.50%
发文量
86
审稿时长
12 months
期刊介绍: The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.
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