Agonist-Mediated Activation of STING Induces Apoptosis in Malignant B Cells

Endoplasmic reticulum (ER) stress responses through the IRE-1/XBP-1 pathway are required for the function of STING (TMEM173), an ER-resident transmembrane protein critical for cytoplasmic DNA sensing, IFN production, and cancer control. Here we show that the IRE-1/XBP-1 pathway functions downstream...

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Veröffentlicht in:Cancer research (Chicago, Ill.) Jg. 76; H. 8; S. 2137
Hauptverfasser: Tang, Chih-Hang Anthony, Zundell, Joseph A, Ranatunga, Sujeewa, Lin, Cindy, Nefedova, Yulia, Del Valle, Juan R, Hu, Chih-Chi Andrew
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 15.04.2016
Schlagworte:
Animals
Apoptosis - physiology
B-Lymphocytes - cytology
B-Lymphocytes - metabolism
Cell Line
Cyclic GMP - administration & dosage
Cyclic GMP - pharmacology
Injections, Intraperitoneal
Membrane Proteins - agonists
Membrane Proteins - physiology
Mice
ISSN:1538-7445, 1538-7445
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Zusammenfassung:Endoplasmic reticulum (ER) stress responses through the IRE-1/XBP-1 pathway are required for the function of STING (TMEM173), an ER-resident transmembrane protein critical for cytoplasmic DNA sensing, IFN production, and cancer control. Here we show that the IRE-1/XBP-1 pathway functions downstream of STING and that STING agonists selectively trigger mitochondria-mediated apoptosis in normal and malignant B cells. Upon stimulation, STING was degraded less efficiently in B cells, implying that prolonged activation of STING can lead to apoptosis. Transient activation of the IRE-1/XBP-1 pathway partially protected agonist-stimulated malignant B cells from undergoing apoptosis. In Eμ-TCL1 mice with chronic lymphocytic leukemia, injection of the STING agonist 3'3'-cGAMP induced apoptosis and tumor regression. Similarly efficacious effects were elicited by 3'3'-cGAMP injection in syngeneic or immunodeficient mice grafted with multiple myeloma. Thus, in addition to their established ability to boost antitumoral immune responses, STING agonists can also directly eradicate malignant B cells. Cancer Res; 76(8); 2137-52. ©2016 AACR.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:1538-7445
1538-7445
DOI:10.1158/0008-5472.CAN-15-1885