E1A Oncogene Enhancement of Caspase-2-Mediated Mitochondrial Injury Sensitizes Cells to Macrophage Nitric Oxide-Induced Apoptosis

Abstract

The adenovirus E1A oncogene induces innate immune rejection of tumors by sensitizing tumor cells to apoptosis in response to injuries, such as those inflicted by macrophage-produced TNF α and NO. E1A sensitizes cells to TNF by repressing its activation of NF-κB-dependent, antiapoptotic defenses. This suggested the hypothesis that E1A blockade of the NF-κB activation response might be the central mechanism of E1A induced cellular sensitivity to other proapoptotic injuries, such as macrophage-produced NO. However, creation of E1A-positive NIH-3T3 mouse cell variants with high-level, NF-κB-dependent resistance to TNF did not coselect for resistance to apoptosis induced by either macrophage-NO or chemical-NO, as the hypothesis would predict. E1A expression did block cellular recovery from NO-induced mitochondrial injury and converted the reversible, NO-induced cytostasis response of cells to an apoptotic response. This viral oncogene-induced phenotypic conversion of the cellular injury response of mouse and human cells was mediated by an E1A-related increase in NO-induced activation of caspase-2, an apical initiator of intrinsic apoptosis. Blocking caspase-2 activation or expression eliminated the NO-induced apoptotic response of E1A-positive cells. These results define an NF-κB-independent pathway through which the E1A gene of human adenovirus sensitizes mouse and human cells to apoptosis by enhancement of caspase-2-mediated mitochondrial injury.

Caspase-2: controversial killer or checkpoint controller?

“…More recent data have provided additional evidence that caspase-2 influences the cell cycle. MEFs derived from caspase-2 knockout mice proliferated substantially faster than wild type cells [58], an effect that was exaggerated in MEF lines transformed with the oncogenes E1A (which promotes caspase-2 upregulation [25]) and Ras [58]. As discussed above, caspase-2 knockout mice develop normally [19,55] and transplantation of foetal liver cells from knockout and normal mice into irradiated recipients yielded equivalent cellularity in haemopoietic compartments [65].…”

“…Interestingly, caspase-1 has also been implicated in lipid synthesis, through indirect induction of SREBP processing and activation [24]. Expression Calculated using the protein-protein basic local alignment search tool (BLAST) [179,180] relative to CED-3 (NP_502538) of the adenoviral oncogene E1A boosted levels of caspase-2 protein in murine (but not human) fibroblasts, through an unknown mechanism [25]. It was recently reported that p53 and p73 could repress caspase-2 mRNA and protein expression, in a p21-dependent manner [26].…”

Adenovirus-Based Gene Therapy for Cancer

“…In addition, the E1a antitumor effect may be involved in many genetic factors in cancer cells, including E1a-induced apoptosis (Radke et al, 2008), Ela-enhanced sensitivity to chemotherapeutics and radiation (Sánchez-Prieto et al, 1996), E1a-triggered accumulation of p53 product and the E1a-mediated down-regulation of the oncogene Neu (ErbB-2/HER2) expression (Bartholomeusz et al, 2005;Madhusudan et al, 2004). Neu protein is a member of epidermal growth factor receptor (EGFR) and is commonly overexpressed in many human solid cancers, eg.…”

Adenovirus E1B 19-Kilodalton Protein Modulates Innate Immunity through Apoptotic Mimicry

“…Unfixed corpses were collected and prepared for flow cytometry by washing in PBS ϩ 3% FBS and staining with Hoechst dye and propidium iodide (PI) (14). Externalization of phosphatidylserine residues on the outer plasma membranes of apoptotic cells was assayed by staining CPE corpses with anti-annexin V antibody and 7-amino actinomycin D (7-AAD) according to the manufacturer's recommendations (BD Pharmingen).…”