GDF15 induces chemoresistance to oxaliplatin by forming a reciprocal feedback loop with Nrf2 to maintain redox homeostasis in colorectal cancer

IF 6.6 2区 医学 Q1 Medicine
Haiping Lin, Yang Luo, Tingyue Gong, Hongsheng Fang, Hao Li, Guangyao Ye, Yan Zhang, Ming Zhong
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引用次数: 0

Abstract

Purpose

Growth differentiating Factor 15 (GDF15) is linked to several cancers, but its effect on chemoresistance in colorectal cancer (CRC) remains unclear. Here, we investigated the role of GDF15 in the chemotherapeutic response of CRC patients to oxaliplatin (L-OHP).

Methods

GDF15 levels in serum and tumour tissues were detected in CRC patients have received L-OHP-based neoadjuvant chemotherapy. The effects of GDF15 neutralization or GDF15 knockdown on cell proliferation, apoptosis and intracellular reactive oxygen species (ROS) levels were analysed in vitro and in vivo. Co-immunoprecipitation (Co-IP), Chromatin Immunoprecipitation (ChIP) and luciferase reporter assays were used to explore the interaction between GDF15 and Nrf2.

Results

In this study, we found that GDF15 alleviates oxidative stress to induce chemoresistance of L-OHP in CRC. Mechanically, GDF15 posttranscriptionally regulates protein stability of Nrf2 through the canonical PI3K/AKT/GSK3β signaling pathway, and in turn, Nrf2 acts as a transcription factor to regulate GDF15 expression to form a positive feedback loop, resulting in the maintenance of redox homeostasis balance in CRC. Furthermore, a positive correlation between GDF15 and Nrf2 was observed in clinical CRC samples, and simultaneous overexpression of both GDF15 and Nrf2 was associated with poor prognosis in CRC patients treated with L-OHP. Simultaneous inhibition of both GDF15 and Nrf2 significantly increases the response to L-OHP in an L-OHP-resistant colorectal cancer cells-derived mouse xenograft model.

Conclusion

This study identified a novel GDF15-Nrf2 positive feedback loop that drives L-OHP resistance and suggested that the GDF15-Nrf2 axis is a potential therapeutic target for the treatment of L-OHP-resistant CRC.

Graphical Abstract

Abstract Image

GDF15 通过与 Nrf2 形成互惠反馈环路来维持结直肠癌的氧化还原平衡,从而诱导对奥沙利铂的化疗耐药性
目的 生长分化因子15(GDF15)与多种癌症有关,但它对结直肠癌(CRC)化疗耐药性的影响仍不清楚。方法 在接受了以奥沙利铂(L-OHP)为基础的新辅助化疗的 CRC 患者中检测血清和肿瘤组织中的 GDF15 水平。在体外和体内分析了GDF15中和或GDF15敲除对细胞增殖、凋亡和细胞内活性氧(ROS)水平的影响。结果在这项研究中,我们发现GDF15能减轻氧化应激,从而诱导CRC对L-OHP的化疗抵抗。从机理上讲,GDF15通过典型的PI3K/AKT/GSK3β信号通路转录后调节Nrf2的蛋白稳定性,而Nrf2又作为转录因子调节GDF15的表达,形成正反馈环,从而维持CRC的氧化还原平衡。此外,GDF15和Nrf2在临床CRC样本中呈正相关,GDF15和Nrf2同时过表达与接受L-OHP治疗的CRC患者预后不良有关。结论这项研究发现了一种新型的GDF15-Nrf2正反馈环路,它能驱动L-OHP耐药,并提示GDF15-Nrf2轴是治疗L-OHP耐药CRC的潜在治疗靶点。
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来源期刊
Cellular Oncology
Cellular Oncology Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
10.40
自引率
1.50%
发文量
0
审稿时长
16 weeks
期刊介绍: The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.
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