Tumor-associated macrophages confer colorectal cancer 5-fluorouracil resistance by promoting MRP1 membrane translocation via an intercellular CXCL17/CXCL22-CCR4-ATF6-GRP78 axis.
Tumor-associated macrophages confer colorectal cancer 5-fluorouracil resistance by promoting MRP1 membrane translocation via an intercellular CXCL17/CXCL22-CCR4-ATF6-GRP78 axis.
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DOI：
10.1038/s41419-023-06108-0
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发表时间：
2023-09-01
影响因子：
9
通讯作者：
Li, Zhuoyu
中科院分区：
文献类型：
--
作者：
Zhang, Lichao;Lu, Xiaoqing;Xu, Yuanzhi;La, Xiaoqin;Tian, Jinmiao;Li, Aiping;Li, Hanqing;Wu, Changxin;Xi, Yanfeng;Song, Guisheng;Zhou, Zhaocai;Bai, Wenqi;An, Liwei;Li, Zhuoyu
化疗是结直肠癌(CRC)临床治疗的主要类型。转运蛋白介导的异常药物外排是肿瘤细胞获得化疗耐药的关键途径。越来越多的证据表明，肿瘤相关巨噬细胞(TAMs)在肿瘤的发生和耐药中发挥着关键作用。然而，TAMs调节药物外流的具体机制仍然不清楚。在这里，我们发现TAMS通过细胞间相互作用介导的MRP1依赖的药物外排过程使CRC细胞对5-氟尿嘧啶(5-FU)产生耐药性。在机制上，分泌的C-C基序趋化因子配体17和CCL22通过膜受体CCR4激活结直肠癌细胞的PI3K/AKT通路。具体地说，AKT的磷酸化使IP3R失活，并诱导内质网钙聚集，导致ATF6激活和GRP78上调。因此，过量的GRP78可以与MRP1相互作用，促进其移位到细胞膜，导致诱导的5-FU外流。综上所述，我们的结果表明TAMs通过上调GRP78的表达促进MRP1膜转位和药物外排，从而促进结直肠癌的化疗耐药，为诱导耐药提供了直接的证据。
Chemotherapy represents a major type of clinical treatment against colorectal cancer (CRC). Aberrant drug efflux mediated by transporters acts as a key approach for tumor cells to acquire chemotherapy resistance. Increasing evidence implies that tumor-associated macrophages (TAMs) play a pivotal role in both tumorigenesis and drug resistance. Nevertheless, the specific mechanism through which TAMs regulate drug efflux remains elusive. Here, we discovered that TAMs endow CRC cells with resistance to 5-fluorouracil (5-FU) treatment via a cell-cell interaction-mediated MRP1-dependent drug efflux process. Mechanistically, TAM-secreted C-C motif chemokine ligand 17 (CCL17) and CCL22, via membrane receptor CCR4, activated the PI3K/AKT pathway in CRC tumor cells. Specifically, phosphorylation of AKT inactivated IP3R and induced calcium aggregation in the ER, resulting in the activation of ATF6 and upregulation of GRP78. Accordingly, excessive GRP78 can interact with MRP1 and promote its translocation to the cell membrane, causing TAM-induced 5-FU efflux. Taken together, our results demonstrated that TAMs promote CRC chemotherapy resistance via elevating the expression of GRP78 to promote the membrane translocation of MRP1 and drug efflux, providing direct proof for TAM-induced drug resistance.
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肿瘤相关巨噬细胞促进肿瘤进展的新机制：最新研究进展和肿瘤免疫治疗的潜在靶点
影响因子：
4.1
作者：
Guo Q;Jin Z;Yuan Y;Liu R;Xu T;Wei H;Xu X;He S;Chen S;Shi Z;Hou W;Hua B
通讯作者：
Hua B
影响因子：
5.8
作者：
Bailly, Christian;Waring, Michael J.
通讯作者：
Waring, Michael J.
影响因子：
64.5
作者：
Cubillos-Ruiz JR;Bettigole SE;Glimcher LH
通讯作者：
Glimcher LH
影响因子：
4.3
作者：
Casas C
通讯作者：
Casas C
DOI：
10.1084/jem.20150295
发表时间：
2015-04-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Mantovani A;Allavena P
通讯作者：
Allavena P