Apoptin acts as a tumor-specific killer: potentials for an anti-tumor therapy.
Apoptin, a protein encoded by an avian virus, induces apoptosis in a tumor-specific way, acts p53-independently and is even stimulated by the anti-apoptotic protein Bcl-2. Activation of upstream caspases is not required, whereas the activation of downstream caspases is involved in rapid Apoptin-induced cell death. Yet, in a caspase-3-negative human breast cancer cell line, Apoptin can induce apoptosis, but delayed. These features indicate that Apoptin can induce apoptosis via multiple pathways in tumor cells when other agents might fail. Apoptin is biologically active as a highly stable, multimeric complex, consisting of 30 to 40 monomers and forms cooperatively distinct superstructures upon binding to DNA. In tumor cells, Apoptin is imported into the nucleus prior to the induction of apoptosis; this contrasts with the situation in primary, normal cell cultures where nuclear import of Apoptin is very rare. Apoptin contains two different domains that induce apoptosis independently, and for both domains, a strong correlation exists between nuclear localization and killing activity. Apoptin is regulated by a kinase activity present in cancer cells but negligible in normal cells. Apoptin interacts with various partners of the human proteome such as DEDAF, which when overexpressed induces apoptosis in various human tumor cell lines but not in primary human cells, similar to Apoptin. In normal cells, Apoptin becomes aggregated, epitope shielded and eventually degraded in the cytoplasm. Furthermore, Apoptin-transgenic mice and other animal models have revealed Apoptin as a safe and efficient anti-tumor agent. These in vitro and in vivo tumor-specific features of Apoptin imply that it can form the basis of future anti-tumor therapies.
Noteborn
M H M
MH
Molecular Cell Biology, Leiden University Medical Center, 2300 RA, Leiden, The Netherlands. m.noteborn@chem.leidenuniv.nl
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D036022:Capsid Proteins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*; D020169:Caspases / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*
D000970:Antineoplastic Agents; D036022:Capsid Proteins; C091717:VP3 protein, Chicken anemia virus; D020169:Caspases