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

中文翻译：

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GDF15 通过与 Nrf2 形成交互反馈环来维持结直肠癌中的氧化还原稳态，从而诱导奥沙利铂化疗耐药

目的

生长分化因子 15 (GDF15) 与多种癌症有关，但其对结直肠癌 (CRC) 化疗耐药性的影响仍不清楚。在这里，我们研究了 GDF15 在 CRC 患者对奥沙利铂 (L-OHP) 化疗反应中的作用。

方法

在接受L-OHP为基础的新辅助化疗的CRC患者中检测了血清和肿瘤组织中GDF15的水平。体外和体内分析了 GDF15 中和或 GDF15 敲低对细胞增殖、凋亡和细胞内活性氧 (ROS) 水平的影响。使用免疫共沉淀 (Co-IP)、染色质免疫沉淀 (ChIP) 和荧光素酶报告基因测定来探索 GDF15 和 Nrf2 之间的相互作用。

结果

在这项研究中，我们发现 GDF15 可以减轻氧化应激，从而诱导 CRC 中 L-OHP 的化疗耐药性。机械上，GDF15通过经典的PI3K/AKT/GSK3β信号通路在转录后调节Nrf2的蛋白稳定性，反过来，Nrf2作为转录因子调节GDF15的表达，形成正反馈环，从而维持细胞内氧化还原稳态平衡。 CRC。此外，在临床 CRC 样本中观察到 GDF15 和 Nrf2 之间呈正相关，并且 GDF15 和 Nrf2 同时过表达与接受 L-OHP 治疗的 CRC 患者预后不良相关。在 L-OHP 抗性结直肠癌细胞来源的小鼠异种移植模型中，同时抑制 GDF15 和 Nrf2 显着增加对 L-OHP 的反应。

结论

这项研究发现了一种新的 GDF15-Nrf2 正反馈环路，可驱动 L-OHP 耐药性，并表明 GDF15-Nrf2 轴是治疗 L-OHP 耐药性 CRC 的潜在治疗靶点。

图形概要