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E1A enhances cellular sensitivity to DNA-damage-induced apoptosis through PIDD-dependent caspase-2 activation
Jay R Radke1, Zeba K Siddiqui2, Iris Figueroa3
1Research Section, Edward Hines, Jr. VA Hospital, 5000 S 5th Ave., Hines, IL 60141, USA; Division of Infectious Diseases, Loyola University Medical Center; Infectious Diseases and Immunology Research Institute, Loyola University Chicago-Stritch School of Medicine, Maywood, IL, USA; Department of Microbiology and Immunology, Loyola University Chicago-Stritch School of Medicine, Maywood, IL, USA.
Cell Death Discovery
|November 12, 2016
Summary
Adenovirus E1A protein sensitizes cells to chemotherapy by activating the PIDD/caspase-2 pathway, leading to mitochondrial injury and apoptosis. This pathway is crucial for E1A-mediated sensitization to DNA-damaging agents like etoposide and gemcitabine.
Area of Science:
- Molecular Biology
- Cellular Biology
- Biochemistry
Background:
- Adenoviral E1A protein induces apoptosis via multiple pathways.
- E1A inhibits NF-kappa B (NF-κB) to sensitize cells to TNF-superfamily members.
- E1A also sensitizes cells to nitric oxide (NO) through caspase-2 activation, independent of NF-κB.
Purpose of the Study:
- To investigate if E1A-induced sensitization to DNA-damaging chemotherapeutic agents involves the caspase-2 pathway.
- To determine the role of caspase-2 and PIDD in E1A-mediated sensitization to etoposide and gemcitabine.
Main Methods:
- Cellular assays measuring apoptosis, caspase activation, and mitochondrial injury.
- Expression of adenoviral E1A protein in mammalian cells.
- Analysis of the role of NF-κB, caspase-2, and PIDD in apoptosis induction.
Main Results:
- E1A-induced sensitization to etoposide and gemcitabine is independent of NF-κB but dependent on caspase-2 activation.
- Caspase-2 is essential for mitochondrial injury and caspase-3 activation during etoposide/gemcitabine-induced apoptosis in E1A-positive cells.
- PIDD expression and cleavage to PIDD-CC are required for caspase-2 activation, mitochondrial injury, and enhanced apoptosis.
Conclusions:
- The PIDD/caspase-2 pathway is a critical apical mechanism mediating E1A-induced sensitization to DNA-damaging chemotherapeutic agents.
- Caspase-2 acts as a key mitochondrial-injuring caspase in this context.
- E1A-enhanced apoptosis sensitivity relies on the integrity of the PIDD/caspase-2 signaling cascade.
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