癌症相关成纤维细胞衍生的乳酸通过促进结直肠癌ANTXR1乳酸化诱导奥沙利铂治疗耐药

IF 10.1 1区医学 Q1 ONCOLOGY

Cancer letters Pub Date : 2025-07-17 DOI:10.1016/j.canlet.2025.217917

Jiahua He , Weihao Li , Song Wang , Jin Lan , Xuanlin Hong , Leen Liao , Da Kang , Weifeng Wang , Ruowei Wang , Weili Zhang , Long Yu , Qingjian Ou , Yujing Fang , Xiaojun Wu , Junzhong Lin , Peirong Ding , Chi Zhou , Zhizhong Pan , Jianhong Peng

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引用次数: 0

摘要

奥沙利铂广泛应用于晚期结直肠癌（CRC）患者的化疗。然而，频繁的耐药限制了其对患者的治疗效果。本研究中，我们发现糖酵解活化的癌相关成纤维细胞（CAFs）亚群诱导结直肠癌对奥沙利铂耐药。来自caf的乳酸通过组蛋白乳酸化促进ANTXR1的转录，并在赖氨酸453残基处诱导ANTXR1的乳酸化。结直肠癌细胞中ANTXR1和ANTXR1 K453la表达升高与结直肠癌细胞对奥沙利铂耐药及结直肠癌患者预后不良相关。在机制上，乳酸化促进了ANTXR1的稳定性，激活了RhoC/ROCK1/SMAD5信号通路，随后促进了CRC的干系性和奥沙利铂耐药性。在体外和细胞/患者来源的异种移植模型中，基因或药物抑制CAFs和癌细胞之间的乳酸穿梭可提高化疗效率。这些发现有助于更好地理解奥沙利铂耐药性，并表明抑制肿瘤-基质相互作用可能是提高奥沙利铂疗效的一种有吸引力的策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Cancer associated fibroblasts-derived lactate induces oxaliplatin treatment resistance by promoting cancer stemness via ANTXR1 lactylation in colorectal cancer

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Cancer associated fibroblasts-derived lactate induces oxaliplatin treatment resistance by promoting cancer stemness via ANTXR1 lactylation in colorectal cancer

Oxaliplatin is widely used in chemotherapy for patients with advanced colorectal cancer (CRC). However, frequent drug resistance limits its therapeutic efficacy in patients. Here, we found that a subset of cancer associated fibroblasts (CAFs) with activated glycolysis induced CRC resistance to oxaliplatin. Lactate derived from CAFs promoted the transcription of ANTXR1 through histone lactylation and induced ANTXR1 lactylation at lysine 453 residue. The increased expression of ANTXR1 and ANTXR1 K453la in CRC cells was correlated with oxaliplatin resistance in CRC cells and the poor prognosis of CRC patients. Mechanistically, lactylation promoted ANTXR1 stability and activated the RhoC/ROCK1/SMAD5 signal pathway, subsequently contributed to CRC stemness and oxaliplatin resistance. Genetic or pharmacologic inhibition of the lactate shuttle between CAFs and cancer cells improved chemotherapy efficiency in vitro and in cell/patient-derived xenograft models. These findings contribute to a better understanding of oxaliplatin resistance and indicates that inhibition of tumor-stromal interactions might be an attractive strategy for enhancing the efficacy of oxaliplatin.

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来源期刊

Cancer letters 医学-肿瘤学

CiteScore

17.70

自引率

2.10%

发文量

427

审稿时长

15 days

期刊介绍： Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.