B cell cancer, endoplasmic reticulum, IRE-1; STING, XBP-1
Digital Object Identifier (DOI)
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.
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Citation / Publisher Attribution
Cancer Research, v. 76, issue 8, p. 2137-2152
Scholar Commons Citation
Tang, Chih-Hang Anthony; Zundell, Joseph A.; Ranatunga, Sujeewa; Lin, Cindy; Nefedova, Yulia; Del Valle, Juan R.; and Hu, Chih-Chi Andrew, "Agonist-Mediated Activation of STING Induces Apoptosis in Malignant B Cells" (2016). Chemistry Faculty Publications. 25.