title: Agonist-Mediated Activation of STING Induces Apoptosis in Malignant B Cells.
abstract: 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.
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Chih-Hang Anthony
authors.initials: CH
authors.lastname: Tang
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Zundell
authors.affiliation: Department of Chemistry, University of South Florida, Tampa, Florida.
authors.forename: Sujeewa
authors.initials: S
authors.lastname: Ranatunga
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Cindy
authors.initials: C
authors.lastname: Lin
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Nefedova
authors.affiliation: Department of Chemistry, University of South Florida, Tampa, Florida.
authors.forename: Juan R
authors.initials: JR
authors.lastname: Del Valle
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania. Chu@wistar.org.
authors.forename: Chih-Chi Andrew
authors.initials: CC
authors.lastname: Hu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002460:Cell Line; D006152:Cyclic GMP / Q000008:administration & dosage / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D008565:Membrane Proteins / Q000819:agonists* / Q000502:physiology; D051379:Mice; D000099197:STING Protein
chemical_list: D006152:Cyclic GMP; D008565:Membrane Proteins; C530855:Sting1 protein, mouse; D000099197:STING Protein