Human-gyrovirus-Apoptin triggers mitochondrial death pathway--Nur77 is required for apoptosis triggering
Wiem Chaabane1, Artur Cieślar-Pobuda2, Mohamed El-Gazzah3
1Department of Clinical and Experimental Medicine (IKE), Division of Cell Biology, and Integrative Regenerative Medicine Center (IGEN), Linköping University, Linköping Sweden; Department of Biology, Faculty of Sciences, Tunis University, Tunis, Tunisia.
Abstract:
The human gyrovirus derived protein Apoptin (HGV-Apoptin) a homologue of the chicken anemia virus Apoptin (CAV-Apoptin), a protein with high cancer cells selective toxicity, triggers apoptosis selectively in cancer cells. In this paper, we show that HGV-Apoptin acts independently from the death receptor pathway as it induces apoptosis in similar rates in Jurkat cells deficient in either FADD (fas-associated death domain) function or caspase-8 (key players of the extrinsic pathway) and their parental clones. HGV-Apoptin induces apoptosis via the activation of the mitochondrial intrinsic pathway. It induces both mitochondrial inner and outer membrane permebilization, characterized by the loss of the mitochondrial potential and the release into cytoplasm of the pro-apoptotic molecules including apoptosis inducing factor and cytochrome c. HGV-Apoptin acts via the apoptosome, as lack of expression of apoptotic protease-activating factor 1 in murine embryonic fibroblast strongly protected the cells from HGV-Apoptin-induced apoptosis. Moreover, QVD-oph a broad-spectrum caspase inhibitor delayed HGV-Apoptin-induced death. On the other hand, overexpression of the anti-apoptotic BCL-XL confers resistance to HGV-Apoptin-induced cell death. In contrast, cells that lack the expression of the pro-apoptotic BAX and BAK are protected from HGV-Apoptin induced apoptosis. Furthermore, HGV-Apoptin acts independently from p53 signal but triggers the cytoplasmic translocation of Nur77. Taking together these data indicate that HGV-Apoptin acts through the mitochondrial pathway, in a caspase-dependent manner but independently from the death receptor pathway.
Insights
Human gyrovirus Apoptin (HGV-Apoptin) selectively induces cancer cell death via the mitochondrial pathway, not the death receptor pathway. This apoptosis is caspase-dependent but independent of p53 signaling.
Area of Science:
- Molecular Biology
- Cell Biology
- Virology
Background:
- Apoptin, a protein derived from human gyrovirus (HGV-Apoptin), exhibits selective toxicity towards cancer cells.
- Chicken anemia virus Apoptin (CAV-Apoptin) is a known homolog with similar properties.
Purpose of the Study:
- To elucidate the specific molecular pathway through which HGV-Apoptin induces apoptosis in cancer cells.
- To determine if HGV-Apoptin's action is dependent on the death receptor or mitochondrial intrinsic pathway.
Main Methods:
- Apoptosis induction was assessed in Jurkat cells with deficiencies in FADD or caspase-8.
- Mitochondrial integrity and release of pro-apoptotic factors were analyzed.
- Apoptotic protease-activating factor 1 (Apaf-1) deficient cells and caspase inhibition were utilized.
- Expression of BCL-XL, BAX, BAK, and p53 involvement was investigated.
Main Results:
- HGV-Apoptin induced apoptosis independently of the death receptor pathway (FADD, caspase-8 deficient cells).
- Apoptosis was mediated through the mitochondrial intrinsic pathway, evidenced by mitochondrial membrane permeabilization and release of cytochrome c and apoptosis-inducing factor.
- HGV-Apoptin-induced apoptosis involved the apoptosome and was caspase-dependent.
- Overexpression of BCL-XL conferred resistance, while BAX/BAK deficiency conferred protection.
- HGV-Apoptin acted independently of p53 but induced Nur77 translocation.
Conclusions:
- HGV-Apoptin triggers cancer cell apoptosis predominantly via the mitochondrial intrinsic pathway.
- The mechanism is caspase-dependent and bypasses the death receptor pathway.
- HGV-Apoptin's action is independent of p53, highlighting its potential as a targeted cancer therapeutic agent.
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