PHGDH通过Hedgehog信号传导驱动结直肠癌5-FU化疗耐药。

IF 12.8 1区 医学 Q1 ONCOLOGY
Caterina Mancini, Giulia Lori, Gianluca Mattei, Marta Iozzo, Dayana Desideri, Fabio Cianchi, Laura Fortuna, Federico Passagnoli, Daniela Massi, Filippo Ugolini, Luca Messerini, Salvatore Piscuoglio, Antonio Pezone, Francesca Magherini, Alessio Biagioni, Tiziano Lottini, Demetra Zambardino, Giuseppina Ivana Truglio, Elena Petricci, Alberto Magi, Annarosa Arcangeli, Luisa Maresca, Barbara Stecca, Erica Pranzini, Maria Letizia Taddei
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引用次数: 0

摘要

背景:磷酸甘油酸脱氢酶(Phosphoglycerate dehydrogenase, PHGDH)是新生丝氨酸合成途径(de novo Serine synthesis pathway, SSP)中的限速酶,这是一种在多种肿瘤中高度调控的过表达途径。具体来说,PHGDH的表达在肿瘤进展的不同阶段受到动态调节,从而促进癌症的侵袭性。先前,我们证明了通过增加外源性摄取或增加PHGDH表达获得的高丝氨酸(Ser)可用性支持结直肠癌(CRC)的5-氟尿嘧啶(5-FU)耐药。除了维持丝氨酸生物合成的代谢作用外,最近还发现了PHGDH的不同“非酶作用”。本研究旨在探讨PHGDH调节CRC中5-FU反应的非酶机制。方法:采用过表达和基因沉默的方法调节人结直肠癌细胞系中PHGDH的表达,探讨该酶在5-FU细胞反应中的作用。已确定的机制已在选定的5-FU耐药细胞系、CRC患者来源的肿瘤组织样本和患者来源的3D类器官中得到验证。对野生型和phgdh沉默细胞系进行转录组学分析,从而确定了phgdh介导的5-FU耐药的途径。在体外和体内的CRC异种移植模型中验证了所鉴定基因的相关性。结果:PHGDH在结直肠癌组织和患者来源的三维类器官中的表达变化很大。一项对结直肠癌患者的回顾性分析强调了PHGDH表达与治疗反应之间的相关性。同时,通过基因沉默/过表达调控PHGDH表达影响CRC细胞系中5-FU的敏感性。对稳定沉默PHGDH的CRC细胞系的转录组学分析证实了Hedgehog (HH)通路的下调。因此,体外和体内研究表明,在CRC异种移植模型中,5-FU和HH通路抑制剂联合治疗强烈阻碍CRC细胞存活和肿瘤生长。结论:PHGDH通过介导HH信号的上调维持CRC中5-FU的耐药;在不同的CRC模型中,靶向PHGDH-HH轴可增加5-FU的敏感性,这表明5-FU/ hh抑制剂联合治疗策略是对抗CRC耐药的有效途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
PHGDH drives 5-FU chemoresistance in colorectal cancer through the Hedgehog signaling.

Background: Phosphoglycerate dehydrogenase (PHGDH) is the rate-limiting enzyme in the de novo Serine synthesis pathway (SSP), a highly regulated pathway overexpressed in several tumors. Specifically, PHGDH expression is dynamically regulated during different stages of tumor progression, promoting cancer aggressiveness. Previously, we demonstrated that high Serine (Ser) availability, obtained by increased exogenous uptake or increased PHGDH expression, supports 5-Fluorouracil (5-FU) resistance in colorectal cancer (CRC). Beyond its metabolic role in sustaining Ser biosynthesis, different "non-enzymatic roles" for PHGDH have recently been identified. The present study aims to investigate non-enzymatic mechanisms through which PHGDH regulates 5-FU response in CRC.

Methods: Overexpression and gene silencing approaches have been used to modulate PHGDH expression in human CRC cell lines to investigate the role of this enzyme in 5-FU cellular response. Identified mechanisms have been validated in selected 5-FU resistant cell lines, CRC patients-derived tumor tissue samples, and patients-derived 3D organoids. Transcriptomic analysis was performed on wild-type and PHGDH-silenced cell lines, allowing the identification of pathways responsible for PHGDH-mediated 5-FU resistance. The relevance of identified genes was validated in vitro and in vivo in a CRC xenograft model.

Results: PHGDH expression is highly variable among CRC tissues and patient-derived 3D organoids. A retrospective analysis of CRC patients highlighted a correlation between PHGDH expression and therapy response. Coherently, the modulation of PHGDH expression by gene silencing/overexpression affects 5-FU sensitivity in CRC cell lines. Transcriptomic analysis on CRC cell lines stably silenced for PHGDH evidenced down regulation in Hedgehog (HH) pathway. Accordingly, in vitro and in vivo studies demonstrated that the combined treatment of 5-FU and HH pathway inhibitors strongly hinders CRC cell survival and tumor growth in CRC xenograft models.

Conclusions: PHGDH sustains 5-FU resistance in CRC by mediating the upregulation of the HH signaling; targeting the here identified PHGDH-HH axis increases 5-FU susceptibility in different CRC models suggesting the 5-FU/HH-inhibitors combinatorial therapeutic strategy as a valid approach to counteract drug resistance in CRC.

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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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