1. Tumor-associated macrophage (TAM)-secreted CCL22 confers cisplatin resistance of esophageal squamous cell carcinoma (ESCC) cells via regulating the activity of diacylglycerol kinase α (DGKα)/NOX4 axis.
- Author
-
Chen J, Zhao D, Zhang L, Zhang J, Xiao Y, Wu Q, Wang Y, and Zhan Q
- Subjects
- Humans, Cisplatin pharmacology, Cisplatin therapeutic use, Diacylglycerol Kinase genetics, Diacylglycerol Kinase pharmacology, Tumor-Associated Macrophages, NADPH Oxidase 4 genetics, Reactive Oxygen Species, RNA, Small Interfering genetics, Cell Proliferation, Chemokines pharmacology, Chemokines therapeutic use, Cell Line, Tumor, Chemokine CCL22 pharmacology, Chemokine CCL22 therapeutic use, Esophageal Squamous Cell Carcinoma drug therapy, Esophageal Squamous Cell Carcinoma genetics, Esophageal Squamous Cell Carcinoma pathology, Esophageal Neoplasms drug therapy, Esophageal Neoplasms genetics, Esophageal Neoplasms metabolism, Carcinoma, Squamous Cell drug therapy, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell metabolism
- Abstract
Tumor-associated macrophages (TAMs) are often associated with chemoresistance and resultant poor clinical outcome in solid tumors. Here, we demonstrated that TAMs-released chemokine-C-C motif chemokine 22 (CCL22) in esophageal squamous cell carcinoma (ESCC) stroma was tightly correlated with the chemoresistance of ESCC patients. TAMs-secreted CCL22 was able to block the growth inhibitory and apoptosis-promoting effects of cisplatin on ESCC cells. Mechanistically, CCL22 stimulated intratumoral diacylglycerol kinase α (DGKα) to produce phosphatidic acid (PA), which suppressed the activity of NADPH oxidase 4 (NOX4) and then blocked the overproduction of intratumoral reactive species oxygen (ROS) induced by cisplatin. CCL22 activated DGKα/nuclear factor-κB (NF-κB) axis to upregulate the level of several members of ATP binding cassette (ABC) transporter superfamily, including ABC sub-family G member 4 (ABCG4), ABC sub-family A member 3 (ABCA3), and ABC sub-family A member 5 (ABCA5), to lower the intratumoral concentration of cisplatin. Consequently, these processes induced the cisplatin resistance in ESCC cells. In xenografted models, targeting DGKα with 5'-cholesterol-conjugated small-interfering (si) RNA enhanced the chemosensitivity of cisplatin in ESCC treatment, especially in the context of TAMs. Our data establish the correlation between the TAMs-induced intratumoral metabolic product/ROS axis and chemotherapy efficacy in ESCC treatment and reveal relevant molecular mechanisms., Competing Interests: Declaration of Competing Interest The authors have declared that no competing interest exists., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF