Cargando…
Semisynthesis reveals apoptin as a tumour-selective protein prodrug that causes cytoskeletal collapse
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 a...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society of Chemistry
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10074440/ https://www.ncbi.nlm.nih.gov/pubmed/37035694 http://dx.doi.org/10.1039/d2sc04481a |
_version_ | 1785019757712375808 |
---|---|
author | Wyatt, Jasmine Chan, Yuen Ka Hess, Mateusz Tavassoli, Mahvash Müller, Manuel M. |
author_facet | Wyatt, Jasmine Chan, Yuen Ka Hess, Mateusz Tavassoli, Mahvash Müller, Manuel M. |
author_sort | Wyatt, Jasmine |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-10074440 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | The Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-100744402023-04-06 Semisynthesis reveals apoptin as a tumour-selective protein prodrug that causes cytoskeletal collapse Wyatt, Jasmine Chan, Yuen Ka Hess, Mateusz Tavassoli, Mahvash Müller, Manuel M. Chem Sci Chemistry 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. The Royal Society of Chemistry 2023-03-16 /pmc/articles/PMC10074440/ /pubmed/37035694 http://dx.doi.org/10.1039/d2sc04481a Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/ |
spellingShingle | Chemistry Wyatt, Jasmine Chan, Yuen Ka Hess, Mateusz Tavassoli, Mahvash Müller, Manuel M. Semisynthesis reveals apoptin as a tumour-selective protein prodrug that causes cytoskeletal collapse |
title | Semisynthesis reveals apoptin as a tumour-selective protein prodrug that causes cytoskeletal collapse |
title_full | Semisynthesis reveals apoptin as a tumour-selective protein prodrug that causes cytoskeletal collapse |
title_fullStr | Semisynthesis reveals apoptin as a tumour-selective protein prodrug that causes cytoskeletal collapse |
title_full_unstemmed | Semisynthesis reveals apoptin as a tumour-selective protein prodrug that causes cytoskeletal collapse |
title_short | Semisynthesis reveals apoptin as a tumour-selective protein prodrug that causes cytoskeletal collapse |
title_sort | semisynthesis reveals apoptin as a tumour-selective protein prodrug that causes cytoskeletal collapse |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10074440/ https://www.ncbi.nlm.nih.gov/pubmed/37035694 http://dx.doi.org/10.1039/d2sc04481a |
work_keys_str_mv | AT wyattjasmine semisynthesisrevealsapoptinasatumourselectiveproteinprodrugthatcausescytoskeletalcollapse AT chanyuenka semisynthesisrevealsapoptinasatumourselectiveproteinprodrugthatcausescytoskeletalcollapse AT hessmateusz semisynthesisrevealsapoptinasatumourselectiveproteinprodrugthatcausescytoskeletalcollapse AT tavassolimahvash semisynthesisrevealsapoptinasatumourselectiveproteinprodrugthatcausescytoskeletalcollapse AT mullermanuelm semisynthesisrevealsapoptinasatumourselectiveproteinprodrugthatcausescytoskeletalcollapse |