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Proteasome inhibitor b-AP15 induces enhanced proteotoxicity by inhibiting cytoprotective aggresome formation

Ellin-Kristina Hillert1, Slavica Brnjic1, Xiaonan Zhang1

  • 1Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.

Cancer Letters
|February 16, 2019
PubMed

Insights

The proteasome inhibitor b-AP15 causes cancer cell death by blocking protein aggregate transport, preventing aggresome formation and increasing proteotoxic stress. This mechanism differs from bortezomib and is not enhanced by SAHA.

Area of Science:

  • Cellular Biology
  • Molecular Oncology
  • Biochemistry

Background:

  • Proteasome inhibitors induce cancer cell death via proteotoxic stress.
  • The aggresome pathway sequesters toxic protein aggregates, acting as an escape from proteotoxicity.

Purpose of the Study:

  • To investigate the mechanism of action of b-AP15, a novel proteasomal deubiquitinase inhibitor.
  • To determine if b-AP15 induces aggresome formation and to compare its effects with bortezomib.

Main Methods:

  • Treatment of cancer cells with b-AP15.
  • Analysis of poly-ubiquitinated protein accumulation.
  • Assessment of aggresome formation and organelle transport.
  • Comparison with bortezomib and SAHA treatments.

Main Results:

  • b-AP15 induces poly-ubiquitin accumulation without aggresome formation.
  • b-AP15 inhibits organelle transport, potentially blocking microtubule-dependent transport of protein aggregates.
  • The cytotoxicity of b-AP15 is not enhanced by SAHA, unlike bortezomib.

Conclusions:

  • b-AP15 inhibits the transport of misfolded proteins, preventing aggresome formation.
  • This leads to a potent proteotoxic stress response and cell death.
  • b-AP15 represents a distinct mechanism of proteasome inhibition compared to bortezomib.
Keywords:
DeubiquitinaseUPS inhibitorUbiquitin-proteasome system

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