{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["14(14)"],"submitter":["Wyatt J"],"pubmed_abstract":["Apoptin is a small viral protein capable of inducing cell death selectively in cancer cells. Despite its potential as an anticancer agent, relatively little is known about its mechanism of toxicity and cancer-selectivity. Previous experiments suggest that cancer-selective phosphorylation modulates apoptin toxicity, although a lack of chemical tools has hampered the dissection of underlying mechanisms. Here, we describe structure-function studies with site-specifically phosphorylated apoptin (apoptin-T108ph) in living cells which revealed that Thr108 phosphorylation is the selectivity switch for apoptin toxicity. Mechanistic investigations link T108ph to actin binding, cytoskeletal disruption and downstream inhibition of anoikis-resistance as well as cancer cell invasion. These results establish apoptin as a protein pro-drug, selectively activated in cancer cells by phosphorylation, which disrupts the cytoskeleton and promotes cell death. We anticipate that this mechanism provides a framework for the design of next generation anticancer proteins with enhanced selectivity and potency."],"journal":["Chemical science"],"pagination":["3881-3892"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10074440"],"repository":["biostudies-literature"],"pubmed_title":["Semisynthesis reveals apoptin as a tumour-selective protein prodrug that causes cytoskeletal collapse."],"pmcid":["PMC10074440"],"pubmed_authors":["Chan YK","Tavassoli M","Muller MM","Hess M","Wyatt J"],"additional_accession":[]},"is_claimable":false,"name":"Semisynthesis reveals apoptin as a tumour-selective protein prodrug that causes cytoskeletal collapse.","description":"Apoptin is a small viral protein capable of inducing cell death selectively in cancer cells. Despite its potential as an anticancer agent, relatively little is known about its mechanism of toxicity and cancer-selectivity. Previous experiments suggest that cancer-selective phosphorylation modulates apoptin toxicity, although a lack of chemical tools has hampered the dissection of underlying mechanisms. Here, we describe structure-function studies with site-specifically phosphorylated apoptin (apoptin-T108ph) in living cells which revealed that Thr108 phosphorylation is the selectivity switch for apoptin toxicity. Mechanistic investigations link T108ph to actin binding, cytoskeletal disruption and downstream inhibition of anoikis-resistance as well as cancer cell invasion. These results establish apoptin as a protein pro-drug, selectively activated in cancer cells by phosphorylation, which disrupts the cytoskeleton and promotes cell death. We anticipate that this mechanism provides a framework for the design of next generation anticancer proteins with enhanced selectivity and potency.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Apr","modification":"2025-04-05T12:18:33.534Z","creation":"2025-04-05T12:18:33.534Z"},"accession":"S-EPMC10074440","cross_references":{"pubmed":["37035694"],"doi":["10.1039/d2sc04481a"]}}