Format

Send to

Choose Destination
J Biol Chem. 2014 Sep 26;289(39):27246-63. doi: 10.1074/jbc.M114.590240. Epub 2014 Aug 11.

Chemotherapeutic drugs induce ATP release via caspase-gated pannexin-1 channels and a caspase/pannexin-1-independent mechanism.

Author information

1
Pharmacology.
2
the Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario N6A-SC1, Canada.
3
Pharmacology, From the Departments of Physiology and Biophysics and Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106 and george.dubyak@case.edu.

Abstract

Anti-tumor immune responses have been linked to the regulated release of ATP from apoptotic cancer cells to engage P2 purinergic receptor signaling cascades in nearby leukocytes. We used the Jurkat T cell acute lymphocytic leukemia model to characterize the role of pannexin-1 (Panx1) channels in the release of nucleotides during chemotherapeutic drug-induced apoptosis. Diverse pro-apoptotic drugs, including topoisomerase II inhibitors, kinase inhibitors, and proteosome inhibitors, induced functional activation of Panx1 channels via caspase-3-mediated cleavage of the Panx1 autoinhibitory C-terminal domain. The caspase-activated Panx1 channels mediated efflux of ATP, but also ADP and AMP, with the latter two comprising >90% of the released adenine nucleotide pool as cells transitioned from the early to late stages of apoptosis. Chemotherapeutic drugs also activated an alternative caspase- and Panx1-independent pathway for ATP release from Jurkat cells in the presence of benzyloxycarbonyl-VAD, a pan-caspase inhibitor. Comparison of Panx1 levels indicated much higher expression in leukemic T lymphocytes than in normal, untransformed T lymphoblasts. This suggests that signaling roles for Panx1 may be amplified in leukemic leukocytes. Together, these results identify chemotherapy-activated pannexin-1 channels and ATP release as possible mediators of paracrine interaction between dying tumor cells and the effector leukocytes that mediate immunogenic anti-tumor responses.

KEYWORDS:

ATP; Apoptosis; Caspase; Pannexin; Purinergic Agonist

PMID:
25112874
PMCID:
PMC4175357
DOI:
10.1074/jbc.M114.590240
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center