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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.
- Source :
-
Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy [Drug Resist Updat] 2024 Mar; Vol. 73, pp. 101055. Date of Electronic Publication: 2024 Jan 18. - Publication Year :
- 2024
-
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.<br />Competing Interests: Declaration of Competing Interest The authors have declared that no competing interest exists.<br /> (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1532-2084
- Volume :
- 73
- Database :
- MEDLINE
- Journal :
- Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 38387281
- Full Text :
- https://doi.org/10.1016/j.drup.2024.101055