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Strategies for Tracking Anastasis, A Cell Survival Phenomenon that Reverses Apoptosis
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Proteome-wide CETSA reveals diverse apoptosis-inducing mechanisms converging on an initial apoptosis effector stage

Anderson Daniel Ramos1, Ying Yu Liang2, Olga Surova1

  • 1Department of Oncology-Pathology, Karolinska Institutet, 171 77 Stockholm, Sweden.

Cell Reports
|October 4, 2024
PubMed

Insights

Cancer drugs initiate apoptosis at the nuclear periphery, not the cytosol. This discovery reveals a new cellular vulnerability for targeted cancer therapies, focusing on caspase cascade localization.

Area of Science:

  • Cellular biology
  • Molecular oncology
  • Biochemistry

Background:

  • Apoptosis (programmed cell death) and caspase cascade activation are well-characterized.
  • The precise timing and location of early biochemical events initiating apoptosis remain incompletely understood.

Purpose of the Study:

  • To dissect the cellular biochemistry of early apoptosis stages at a systems level.
  • To identify the initial biochemical effector events and their subcellular localization following apoptosis induction by various cancer drugs.

Main Methods:

  • Utilized integrated modulation of protein interaction states-cellular thermal shift assay (IMPRINTS-CETSA).
  • Developed a novel CETSA-based method to monitor caspase target cleavage.
  • Studied five distinct families of cancer drugs with varying apoptosis-inducing mechanisms.

Main Results:

  • Discovered that early apoptosis biochemistry, induced by all studied drugs, is concentrated in the peripheral nuclear region, not the cytosol.
  • CETSA data revealed that diverse drug mechanisms converge on related biochemical modulations at the nuclear periphery.
  • Identified specific caspase target cleavage patterns associated with nuclear periphery events.

Conclusions:

  • The localization of caspase cascades in apoptosis is more tightly controlled than previously thought.
  • The nuclear periphery represents a critical and previously underappreciated vulnerability for cancer therapies.
  • Findings suggest novel strategies for developing cancer drugs that target nuclear periphery-localized apoptosis pathways.
Keywords:
CETSACP: CancerCP: Cell biologyIAP inhibitorsPI3K inhibitorsapoptosiscancer drugscaspase cleavageglutathione metabolismmass spectrometryproteomicstaxanes

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