CD73 induces gemcitabine resistance in pancreatic ductal adenocarcinoma: A promising target with non-canonical mechanisms
CD73 induces gemcitabine resistance in pancreatic ductal adenocarcinoma: A promising target with non-canonical mechanisms
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CD73 诱导胰腺导管腺癌中的吉西他滨耐药：具有非典型机制的有希望的靶点
DOI：
10.1016/j.canlet.2021.07.024
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发表时间：
2021
期刊：
影响因子：
9.7
通讯作者：
Hao Jihui
中科院分区：
文献类型：
--
作者：
Yu Xiaozhou;Liu Weishuai;Wang Ziyang;Wang Hongwei;Liu Jing;Huang Chongbiao;Zhao Tiansuo;Wang Xiuchao;Gao Song;Ma Ying;Wu Liangliang;Li Xiaofeng;Yang Shengyu;Hao Jihui
CD 73是细胞表面的一种胞外5′-核苷酸酶，是细胞外腺苷的主要酶源。典型地，它通过其代谢物在癌症相关过程中发挥多种作用。作为一个药物靶点，目前正在各种恶性疾病中进行针对CD 73的临床试验。在此，我们报告了CD 73在胰腺导管腺癌（PDAC）中的非外5′-核苷酸酶依赖性功能。我们的研究结果支持PDAC细胞中CD 73的表达升高通过激活AKT促进吉西他滨（GEM）抗性。我们发现，大量的细胞内的CD 73定位在内质网膜。细胞内CD 73与主要拱顶蛋白发生物理相互作用，激活SRC-AKT回路。曲格列酮（TGZ）是一种过氧化物酶体增殖物激活受体γ激动剂，可抑制CD 73的表达。TGZ的施用通过下调PDAC中的CD 73而显著增强对GEM的敏感性。我们的研究结果支持CD 73可以被靶向以克服PDAC中的化疗耐药性。
CD73, a cell surface-localized ecto-5′-nucleotidase, is the major enzymatic source of extracellular adenosine. Canonically, it plays multiple roles in cancer-related processes via its metabolite. As a druggable target, clinical trials targeting CD73 in various malignant diseases are currently ongoing. Here, we report the ecto-5′-nucleotidase-independent functions of CD73 in pancreatic ductal adenocarcinoma (PDAC). Our findings support that the elevated expression of CD73 in PDAC cells promotes gemcitabine (GEM) resistance by activating AKT. We discovered that a large amount of intracellular CD73 are localized in the endoplasmic reticulum membrane. Intracellular CD73 physically interacts with major vault protein to activate the SRC–AKT circuit. Troglitazone (TGZ) is a peroxisome proliferator-activated receptor gamma agonist that could inhibit the expression of CD73. The administration of TGZ markedly enhances sensitivity to GEM via downregulating CD73 in PDAC. Our findings support that CD73 could be targeted to overcome chemoresistance in PDAC.