IDO1-mediated kynurenine production inhibits IGFBP5 signaling to promote 5-fluorouracil-induced senescence escape and chemoresistance in colorectal cancer.

IF 3.6 3区 医学 Q2 ONCOLOGY American journal of cancer research Pub Date : 2024-09-25 eCollection Date: 2024-01-01 DOI:10.62347/XTRC3347
Yu Li, Chao Li, Xufeng Yao, Junjie Lv, Wenjun Li, Rong Fu, Mengyang Chen, Peng Yang, Qian Dai, Wei Wei, Zongwei Li
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Abstract

Cellular senescence is an irreversible state of growth arrest, and induction of senescence is considered a potential therapeutic strategy against cancer. Indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme catabolizing L-tryptophan into kynurenine, plays a key role in tumor immune tolerance. However, the roles of IDO1 in cellular senescence and chemoresistance remain elusive. Herein, we observed a significant elevation of IDO1 expression in colorectal cancer (CRC) tissues compared to non-neoplastic controls, based on both the GEPIA database and mouse model. Functionally, ectopic expression of IDO1 blunted 5-fluorouracil (5-FU)-induced cell senescence and rendered CRC cells more refractory towards 5-FU treatment, whereas IDO1 silencing resulted in opposing effects. Further studies demonstrated that IDO1 overexpression decreased the levels of senescent-related proteins, including p16, p21, p53, and cyclin D1. Mechanistically, the kynurenine released from IDO1-expressing CRC cells inhibited the IGFBP5/p53 signaling pathway, accounting for IDO1-mediated suppression of cell senescence and induction of chemoresistance. Collectively, these data revealed an unrecognized role of IDO1 in senescence escape and chemoresistance via releasing its catabolite kynurenine, implicating that therapeutically targeting IDO1 or IGFBP5/p53 signaling pathway holds great promise for CRC treatment.

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IDO1介导的犬尿氨酸生成抑制了IGFBP5信号传导,从而促进了5-氟尿嘧啶诱导的结直肠癌衰老逃逸和化疗耐药性。
细胞衰老是一种不可逆的生长停滞状态,诱导衰老被认为是一种潜在的癌症治疗策略。吲哚胺 2,3-二氧化酶 1(IDO1)是一种将 L-色氨酸分解成犬尿氨酸的酶,在肿瘤免疫耐受中起着关键作用。然而,IDO1 在细胞衰老和化疗抗性中的作用仍然难以捉摸。在此,我们根据 GEPIA 数据库和小鼠模型观察到,与非肿瘤性对照组相比,结直肠癌(CRC)组织中 IDO1 的表达明显升高。在功能上,IDO1的异位表达会减弱5-氟尿嘧啶(5-FU)诱导的细胞衰老,并使CRC细胞对5-FU治疗更具耐受性,而IDO1沉默则会产生相反的效果。进一步的研究表明,IDO1过表达会降低衰老相关蛋白的水平,包括p16、p21、p53和细胞周期蛋白D1。从机理上讲,IDO1表达的CRC细胞释放的犬尿氨酸抑制了IGFBP5/p53信号通路,是IDO1介导的抑制细胞衰老和诱导化疗抗性的原因。总之,这些数据揭示了IDO1通过释放其代谢产物犬尿氨酸在衰老逃逸和化疗抗性中的一种未被认识的作用,这意味着以IDO1或IGFBP5/p53信号通路为靶点的治疗方法在治疗CRC方面大有可为。
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来源期刊
自引率
3.80%
发文量
263
期刊介绍: The American Journal of Cancer Research (AJCR) (ISSN 2156-6976), is an independent open access, online only journal to facilitate rapid dissemination of novel discoveries in basic science and treatment of cancer. It was founded by a group of scientists for cancer research and clinical academic oncologists from around the world, who are devoted to the promotion and advancement of our understanding of the cancer and its treatment. The scope of AJCR is intended to encompass that of multi-disciplinary researchers from any scientific discipline where the primary focus of the research is to increase and integrate knowledge about etiology and molecular mechanisms of carcinogenesis with the ultimate aim of advancing the cure and prevention of this increasingly devastating disease. To achieve these aims AJCR will publish review articles, original articles and new techniques in cancer research and therapy. It will also publish hypothesis, case reports and letter to the editor. Unlike most other open access online journals, AJCR will keep most of the traditional features of paper print that we are all familiar with, such as continuous volume, issue numbers, as well as continuous page numbers to retain our comfortable familiarity towards an academic journal.
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