细菌 DnaK 降低抗癌药物顺铂和 5FU 的活性。

Bacterial DnaK reduces the activity of anti-cancer drugs cisplatin and 5FU.

机构信息

Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA.

Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA.

出版信息

J Transl Med. 2024 Mar 12;22(1):269. doi: 10.1186/s12967-024-05078-x.

DOI:10.1186/s12967-024-05078-x

PMID:38475767

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10935962/

Abstract

BACKGROUND

Chemotherapy is a primary treatment for cancer, but its efficacy is often limited by cancer-associated bacteria (CAB) that impair tumor suppressor functions. Our previous research found that Mycoplasma fermentans DnaK, a chaperone protein, impairs p53 activities, which are essential for most anti-cancer chemotherapeutic responses.

METHODS

To investigate the role of DnaK in chemotherapy, we treated cancer cell lines with M. fermentans DnaK and then with commonly used p53-dependent anti-cancer drugs (cisplatin and 5FU). We evaluated the cells' survival in the presence or absence of a DnaK-binding peptide (ARV-1502). We also validated our findings using primary tumor cells from a novel DnaK knock-in mouse model. To provide a broader context for the clinical significance of these findings, we investigated human primary cancer sequencing datasets from The Cancer Genome Atlas (TCGA). We identified F. nucleatum as a CAB carrying DnaK with an amino acid composition highly similar to M. fermentans DnaK. Therefore, we investigated the effect of F. nucleatum DnaK on the anti-cancer activity of cisplatin and 5FU.

RESULTS

Our results show that both M. fermentans and F. nucleatum DnaKs reduce the effectiveness of cisplatin and 5FU. However, the use of ARV-1502 effectively restored the drugs' anti-cancer efficacy.

CONCLUSIONS

Our findings offer a practical framework for designing and implementing novel personalized anti-cancer strategies by targeting specific bacterial DnaKs in patients with poor response to chemotherapy, underscoring the potential for microbiome-based personalized cancer therapies.

摘要

背景

化疗是癌症的主要治疗方法，但由于癌症相关细菌（CAB）的存在，其疗效往往受到限制，这些细菌会损害肿瘤抑制功能。我们之前的研究发现，支原体发酵单胞菌 DnaK 是一种伴侣蛋白，它会损害 p53 的活性，而 p53 对大多数抗癌化疗反应至关重要。

方法

为了研究 DnaK 在化疗中的作用，我们用 M. fermentans DnaK 处理癌细胞系，然后用常用的依赖 p53 的抗癌药物（顺铂和 5FU）处理。我们评估了在存在或不存在 DnaK 结合肽（ARV-1502）的情况下细胞的存活率。我们还使用新型 DnaK 敲入小鼠模型中的原代肿瘤细胞验证了我们的发现。为了为这些发现的临床意义提供更广泛的背景，我们研究了来自癌症基因组图谱（TCGA）的人类原发性癌症测序数据集。我们发现具核梭杆菌是一种携带 DnaK 的 CAB，其氨基酸组成与 M. fermentans DnaK 高度相似。因此，我们研究了 F. nucleatum DnaK 对顺铂和 5FU 抗癌活性的影响。