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Semisynthesis reveals apoptin as a tumour-selective protein prodrug that causes cytoskeletal collapse

Jasmine Wyatt1,2, Yuen Ka Chan1, Mateusz Hess2

  • 1Department of Molecular Oncology, King's College London Guy's Hospital Campus, Hodgkin Building London SE1 1UL UK mahvash.tavassoli@kcl.ac.uk.

Chemical Science
|April 10, 2023
PubMed

Insights

Apoptin protein selectively kills cancer cells by becoming activated through phosphorylation. This process disrupts the cancer cell cytoskeleton, leading to cell death and reduced invasion, offering a new anticancer strategy.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Cell Biology

Background:

  • Apoptin is a viral protein with selective cancer cell-killing properties.
  • Its precise mechanism of action and cancer selectivity remain incompletely understood.
  • Phosphorylation is hypothesized to regulate apoptin's toxicity and selectivity.

Purpose of the Study:

  • To investigate the role of site-specific phosphorylation in apoptin's anticancer activity.
  • To elucidate the molecular mechanisms underlying apoptin's cancer selectivity.
  • To explore the potential of apoptin as a targeted anticancer therapeutic.

Main Methods:

  • Site-specific phosphorylation of apoptin at Thr108 (apoptin-T108ph).
  • Structure-function studies in living cancer cells.
  • Investigation of cellular pathways including actin binding and cytoskeletal integrity.
  • Analysis of anoikis resistance and cancer cell invasion.

Main Results:

  • Thr108 phosphorylation acts as a critical selectivity switch for apoptin toxicity.
  • Phosphorylated apoptin (apoptin-T108ph) binds to actin and disrupts the cytoskeleton.
  • This disruption inhibits anoikis resistance and reduces cancer cell invasion.
  • Apoptin functions as a pro-drug activated by cancer-specific phosphorylation.

Conclusions:

  • Cancer-selective phosphorylation activates apoptin, enhancing its anticancer potency.
  • The mechanism involves cytoskeletal disruption, leading to cancer cell death.
  • This study provides a foundation for developing novel, highly selective protein-based anticancer agents.

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