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First published online September 22, 2005
doi: 10.1242/10.1242/jcs.02580

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Cancer-specific toxicity of apoptin is independent of death receptors but involves the loss of mitochondrial membrane potential and the release of mitochondrial cell-death mediators by a Nur77-dependent pathway

Subbareddy Maddika^1,2,*, Evan P. Booy^1,2,*, Dina Johar^1,2, Spencer B. Gibson^1,2, Saeid Ghavami^1,2 and Marek Los^1,2,3,

¹ Manitoba Institute of Cell Biology, CancerCare Manitoba, University of Manitoba, Winnipeg, MB R3E OV9, Canada
² Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R3E OV9, Canada
³ The Manitoba Institute of Child Health, 715 McDermot Avenue, Winnipeg, MB R3E 3P4, Canada

Author for correspondence (e-mail: losmj{at}cc.umanitoba.ca)

Accepted 13 July 2005

Apoptin, a small proline-rich protein derived from the chicken anaemia virus, induces cell death selectively in cancer cells. The signalling pathways of apoptin-induced, cancer cell-selective apoptosis are not well understood. Here, we demonstrate that apoptin triggers apoptosis by activating the mitochondrial/intrinsic pathway, and that it acts independently of the death receptor/extrinsic pathway. Jurkat cells deficient in either FADD or caspase-8 (which are both necessary for the extrinsic pathway) were equally as sensitive to apoptin as their parental clones. This demonstrates that apoptin is likely to act through the mitochondrial death pathway. Apoptin treatment causes a loss of mitochondrial membrane potential, and release of the mitochondrial proteins cytochrome c and apoptosis-inducing factor. Apoptin-induced cell death is counteracted by the anti-apoptotic Bcl-2 family members, Bcl-2 itself and Bcl-X_L, as shown in Jurkat leukaemia cells. In addition, we describe the processing and activation of caspase-3. By contrast, cleavage of caspase-8, which is predominantly triggered by the death receptor pathway, is not observed. Furthermore, apoptin triggers the cytoplasmic translocation of Nur77, and the inhibition of Nur77 expression by siRNA significantly protects MCF7 cells from apoptin-triggered cell death. Thus, our data indicate that the apoptin death signal(s) ultimately converges at the mitochondria, and that it acts independently of the death receptor pathway.

Key words: AIF, Apoptin, Death receptors, Mitochondrial death pathway, Nur77

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