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在营养匮乏的微环境中，鉴定 STAM 结合蛋白作为吉西他滨耐药胰腺癌治疗靶点。

Identification of STAM-binding protein as a target for the treatment of gemcitabine resistance pancreatic cancer in a nutrient-poor microenvironment.

机构信息

Department of General Surgery, The Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, 330006, Jiangxi, PR China.

Department of Pharmacology, Nanchang University, 461 Bayi Avenue, Nanchang, 330006, Jiangxi, PR China.

出版信息

Cell Death Dis. 2024 Sep 6;15(9):657. doi: 10.1038/s41419-024-07048-z.

DOI:10.1038/s41419-024-07048-z
PMID:39242557
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11379802/
Abstract

Pancreatic cancer (PC) is a highly malignant solid tumor whose resistance to gemcitabine (GEM) chemotherapy is a major cause of poor patient prognosis. Although PC is known to thrive on malnutrition, the mechanism underlying its chemotherapy resistance remains unclear. The current study analyzed clinical tissue sample databases using bioinformatics tools and observed significantly upregulated expression of the deubiquitinase STAMBP in PC tissues. Functional experiments revealed that STAMBP knockdown remarkably increases GEM sensitivity in PC cells. Multiple omics analyses suggested that STAMBP enhances aerobic glycolysis and suppresses mitochondrial respiration to increase GEM resistance in PC both in vitro and in vivo. STAMBP knockdown decreased PDK1 levels, an essential regulator of the aerobic glycolytic process, in several cancers. Mechanistically, STAMBP promoted the PDK1-mediated Warburg effect and chemotherapy resistance by modulating E2F1 via direct binding to E2F1 and suppressing its degradation and ubiquitination. High-throughput compound library screening using three-dimensional protein structure analysis and drug screening identified the FDA drug entrectinib as a potent GEM sensitizer and STAMBP inhibitor, augmenting the antitumor effect of GEM in a patient-derived xenograft (PDX) model. Overall, we established a novel mechanism, via the STAMBP-E2F1-PDK1 axis, by which PC cells become chemoresistant in a nutrient-poor tumor microenvironment.

摘要

胰腺癌（PC）是一种高度恶性的实体肿瘤，对吉西他滨（GEM）化疗的耐药性是导致患者预后不良的主要原因。尽管已知 PC 依赖营养不良而生长，但化疗耐药性的机制仍不清楚。本研究使用生物信息学工具分析了临床组织样本数据库，观察到 PC 组织中去泛素化酶 STAMBP 的表达显著上调。功能实验表明，STAMBP 敲低可显著提高 PC 细胞对 GEM 的敏感性。多项组学分析表明，STAMBP 通过直接结合 E2F1 并抑制其降解和泛素化，增强有氧糖酵解并抑制线粒体呼吸，从而增加 PC 细胞和体内的 GEM 耐药性。STAMBP 敲低降低了几种癌症中有氧糖酵解过程的必需调节剂 PDK1 的水平。在机制上，STAMBP 通过与 E2F1 直接结合并抑制其降解和泛素化，促进 E2F1 介导的 PDK1 依赖性沃伯格效应和化疗耐药性。使用三维蛋白质结构分析和药物筛选的高通量化合物文库筛选鉴定出 FDA 药物恩曲替尼（entrectinib）是一种有效的 GEM 增敏剂和 STAMBP 抑制剂，在患者来源的异种移植（PDX）模型中增强了 GEM 的抗肿瘤作用。总之，我们通过 STAMBP-E2F1-PDK1 轴建立了一种新的机制，即在营养匮乏的肿瘤微环境中，PC 细胞通过该机制变得对化疗耐药。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dc8c/11379802/00a6b3ab854a/41419_2024_7048_Fig10_HTML.jpg
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