Short term starvation potentiates the efficacy of chemotherapy in triple negative breast cancer via metabolic reprogramming.
Short term starvation potentiates the efficacy of chemotherapy in triple negative breast cancer via metabolic reprogramming.
复制标题
DOI：
10.1186/s12967-023-03935-9
复制
发表时间：
2023-03-03
影响因子：
7.4
通讯作者：
Frisan, Teresa
中科院分区：
文献类型：
--
作者：
Pateras, Ioannis S.;Williams, Chloe;Gianniou, Despoina D.;Margetis, Aggelos T.;Avgeris, Margaritis;Rousakis, Pantelis;Legaki, Aigli-Ioanna;Mirtschink, Peter;Zhang, Wei;Panoutsopoulou, Konstantina;Delis, Anastasios D.;Pagakis, Stamatis N.;Tang, Wei;Ambs, Stefan;Berglund, Ulrika Warpman;Helleday, Thomas;Varvarigou, Anastasia;Chatzigeorgiou, Antonios;Nordstrom, Anders;Tsitsilonis, Ourania E.;Trougakos, Ioannis P.;Gilthorpe, Jonathan D.;Frisan, Teresa
关键词：
化疗（CT）是治疗三阴性乳腺癌（TNBC）的核心，但药物毒性和耐药性对治疗方案有很大的限制。禁食可使癌细胞对一系列化疗药物敏感，并改善CT相关的不良反应。然而，禁食或短期饥饿（STS）提高CT疗效的分子机制特征不佳。通过细胞活力和完整性测定（Hoechst和PI染色、MTT或H2 DCFDA染色、免疫荧光）、代谢谱（Seahorse分析、代谢组学）、基因表达（定量实时PCR）和iRNA介导的沉默来评估乳腺癌或接近正常的细胞系对STS和CT组合的差异反应。通过来自患者数据库的转录组数据的生物信息学整合来评价体外数据的临床意义：癌症基因组图谱（TCGA）、欧洲基因组-表型组档案（EGA）、基因表达综合（GEO）和TNBC队列。我们通过建立小鼠同基因原位乳腺肿瘤模型进一步检查了我们的发现在体内的可转化性。我们提供了机制的见解如何预处理STS增强乳腺癌细胞对CT的易感性。我们发现，与接近正常的细胞相比，STS和CT的组合增强了细胞死亡并增加了活性氧（ROS）水平，与TNBC细胞中更高水平的DNA损伤和NRF 2靶基因NQO 1和TXNRD 1的mRNA水平降低相关。活性氧增强与线粒体呼吸受损和代谢谱变化有关，这具有重要的临床预后和预测价值。此外，我们在TNBC小鼠模型中验证了周期性低热量饮食和CT组合的安全性和有效性。我们的体外，体内和临床研究结果提供了一个强大的理论基础，临床试验的治疗效益，短期热量限制作为辅助CT在三重乳腺癌治疗。在线版本包含补充材料，可通过10.1186/s12967-023-03935-9获得。
Chemotherapy (CT) is central to the treatment of triple negative breast cancer (TNBC), but drug toxicity and resistance place strong restrictions on treatment regimes. Fasting sensitizes cancer cells to a range of chemotherapeutic agents and also ameliorates CT-associated adverse effects. However, the molecular mechanism(s) by which fasting, or short-term starvation (STS), improves the efficacy of CT is poorly characterized. The differential responses of breast cancer or near normal cell lines to combined STS and CT were assessed by cellular viability and integrity assays (Hoechst and PI staining, MTT or H2DCFDA staining, immunofluorescence), metabolic profiling (Seahorse analysis, metabolomics), gene expression (quantitative real-time PCR) and iRNA-mediated silencing. The clinical significance of the in vitro data was evaluated by bioinformatical integration of transcriptomic data from patient data bases: The Cancer Genome Atlas (TCGA), European Genome-phenome Archive (EGA), Gene Expression Omnibus (GEO) and a TNBC cohort. We further examined the translatability of our findings in vivo by establishing a murine syngeneic orthotopic mammary tumor-bearing model. We provide mechanistic insights into how preconditioning with STS enhances the susceptibility of breast cancer cells to CT. We showed that combined STS and CT enhanced cell death and increased reactive oxygen species (ROS) levels, in association with higher levels of DNA damage and decreased mRNA levels for the NRF2 targets genes NQO1 and TXNRD1 in TNBC cells compared to near normal cells. ROS enhancement was associated with compromised mitochondrial respiration and changes in the metabolic profile, which have a significant clinical prognostic and predictive value. Furthermore, we validate the safety and efficacy of combined periodic hypocaloric diet and CT in a TNBC mouse model. Our in vitro, in vivo and clinical findings provide a robust rationale for clinical trials on the therapeutic benefit of short-term caloric restriction as an adjuvant to CT in triple breast cancer treatment. The online version contains supplementary material available at 10.1186/s12967-023-03935-9.
登录
查看更多内容
影响因子：
11.4
作者：
Bortolotti M;Polito L;Battelli MG;Bolognesi A
通讯作者：
Bolognesi A
影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
影响因子：
29
作者：
Brandhorst S;Choi IY;Wei M;Cheng CW;Sedrakyan S;Navarrete G;Dubeau L;Yap LP;Park R;Vinciguerra M;Di Biase S;Mirzaei H;Mirisola MG;Childress P;Ji L;Groshen S;Penna F;Odetti P;Perin L;Conti PS;Ikeno Y;Kennedy BK;Cohen P;Morgan TE;Dorff TB;Longo VD
通讯作者：
Longo VD
影响因子：
4
作者：
Dommerholt, Marleen B.;Dionne, Derek A.;Johnson, James D.
通讯作者：
Johnson, James D.
影响因子：
11.2
作者：
Lee C;Safdie FM;Raffaghello L;Wei M;Madia F;Parrella E;Hwang D;Cohen P;Bianchi G;Longo VD
通讯作者：
Longo VD