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NOD2 通过抑制 TYMS/PLK1 信号轴降低黑色素瘤的化疗耐药性。

NOD2 reduces the chemoresistance of melanoma by inhibiting the TYMS/PLK1 signaling axis.

机构信息

Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, China.

Department of Pathology, The Second Affiliated Hospital of Kunming Medical University, Kunming, China.

出版信息

Cell Death Dis. 2024 Oct 1;15(10):720. doi: 10.1038/s41419-024-07104-8.

DOI:10.1038/s41419-024-07104-8
PMID:39353904
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11445241/
Abstract

Nucleotide-binding oligomerization domain 2 (NOD2) is an immune sensor crucial for eliciting the innate immune responses. Nevertheless, discrepancies exist regarding the effect of NOD2 on different types of cancer. This study aimed to investigate these function of NOD2 in melanoma and its underlying mechanisms. We have validated the tumor suppressor effect of NOD2 in melanoma. NOD2 inhibited the proliferation of melanoma cells, hindering their migration and invasion while promoting the onset of apoptosis. Our study showed that NOD2 expression is closely related to pyrimidine and folate metabolism. NOD2 inhibits thymidylate synthase (TYMS) expression by promoting K48-type ubiquitination modification of TYMS, thereby decreasing the resistance of melanoma cells to 5-fluorouracil (5-FU) and capecitabine (CAP). TYMS was identified to form a complex with Polo-like Kinase 1 (PLK1) and activate the PLK1 signaling pathway. Furthermore, we revealed that the combination of the PLK1 inhibitor volasertib (BI6727) with 5-FU or CAP had a synergistic effect repressing the proliferation, migration, and autophagy of melanoma cells. Overall, our research highlights the protective role of NOD2 in melanoma and suggests that targeting NOD2 and the TYMS/PLK1 signaling axis is a high-profile therapy that could be a prospect for melanoma treatment.

摘要

核苷酸结合寡聚化结构域 2（NOD2）是一种对先天免疫反应至关重要的免疫传感器。然而，关于 NOD2 对不同类型癌症的影响存在差异。本研究旨在探讨 NOD2 在黑色素瘤中的作用及其潜在机制。我们验证了 NOD2 在黑色素瘤中的肿瘤抑制作用。NOD2 抑制黑色素瘤细胞的增殖，阻碍其迁移和侵袭，同时促进细胞凋亡的发生。我们的研究表明，NOD2 的表达与嘧啶和叶酸代谢密切相关。NOD2 通过促进胸苷酸合成酶（TYMS）的 K48 型泛素化修饰来抑制 TYMS 的表达，从而降低黑色素瘤细胞对 5-氟尿嘧啶（5-FU）和卡培他滨（CAP）的耐药性。TYMS 被鉴定与 Polo 样激酶 1（PLK1）形成复合物，并激活 PLK1 信号通路。此外，我们揭示了 PLK1 抑制剂 volasertib（BI6727）与 5-FU 或 CAP 的联合使用具有协同作用，能抑制黑色素瘤细胞的增殖、迁移和自噬。总的来说，我们的研究强调了 NOD2 在黑色素瘤中的保护作用，并表明靶向 NOD2 和 TYMS/PLK1 信号轴是一种有前景的治疗方法，可能成为黑色素瘤治疗的新策略。

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