Yes associated protein 1 promotes resistance to 5-fluorouracil in gastric cancer by regulating GLUT3-dependent glycometabolism reprogramming of tumor-associated macrophages
Yes associated protein 1 promotes resistance to 5-fluorouracil in gastric cancer by regulating GLUT3-dependent glycometabolism reprogramming of tumor-associated macrophages
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DOI：
10.1016/j.abb.2021.108838
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发表时间：
2021-03-16
影响因子：
3.9
通讯作者：
Yao, Xingxing
中科院分区：
文献类型：
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作者：
He, Zhanke;Chen, Da;Yao, Xingxing
抗代谢药5-氟尿嘧啶（5-FU）是一种广泛用于治疗胃癌（GC）的化疗方案。然而，对5-FU的耐药性仍然是临床使用中的主要缺点。肿瘤相关巨噬细胞（tumor associated macrophages，TAMs）参与了肿瘤化疗耐药的形成，但其分子机制尚不清楚。在这里，我们证明，YAP 1是过表达的耐药GC组织相比，敏感的GC组织。此外，由YAP 1过表达的GC分泌的IL-3可以使巨噬细胞极化为M2样表型，并诱导GLUT 3依赖的糖酵解程序。同时，极化的M2巨噬细胞通过分泌CCL 8和激活JAK 1/STAT 3信号通路的磷酸化来增强肿瘤细胞对5-FU的耐药性。
The antimetabolite 5-fluorouracil (5-FU) is a widely used chemotherapy regimen for the treatment of gastric cancer (GC). However, resistance to 5-FU remains a major drawback in the clinical use. The treatments of anti-tumor chemo-agents recruit tumor associated macrophages (TAMs) which are highly implicated in the chemoresistance development, but the underlying molecular mechanism is unclear. Here, we demonstrate that YAP1 is overexpressed in resistant GC tissues compared to sensitive GC tissues. Further, IL-3 secreted by YAP1-overexpressed GC could skew macrophage polarization to M2-like phenotype and inducing GLUT3-depended glycolysis program. Meanwhile, polarized M2 macrophages enhance 5-FU resistance in tumor cells by secreting CCL8 and activating phosphorylation of JAK1/STAT3 signaling pathway.