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Regulation of Bax-dependent apoptosis by mitochondrial deubiquitinase USP30

Ding Yan1,2, Xiaofen Li1,2, Qianqian Yang1,2

  • 1Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, China.

Cell Death Discovery
|August 12, 2021
PubMed

Insights

A new gold compound, aumdubin, effectively inhibits deubiquitinases (DUBs) and induces cancer cell death. This agent targets mitochondrial DUB USP30, promoting apoptosis and offering potential new lung cancer therapies.

Area of Science:

  • Biochemistry
  • Oncology
  • Pharmacology

Background:

  • Deubiquitinases (DUBs) are emerging targets for cancer therapy.
  • Metal compounds can induce cancer cell death by inhibiting DUBs.
  • Auranofin, a gold(I) agent, inhibits proteasomal DUBs and induces cancer cell death.

Purpose of the Study:

  • To investigate the efficacy of aumdubin, a synthetic auranofin derivative, as a DUB inhibitor and anticancer agent.
  • To explore aumdubin's mechanism of action, focusing on its interaction with mitochondrial DUB USP30 and its effect on apoptosis in lung cancer cells.

Main Methods:

  • Comparative analysis of DUB-inhibiting and apoptosis-inducing activities of auranofin and aumdubin in lung cancer cells.
  • Assessment of aumdubin's affinity for mitochondrial DUB USP30.
  • Evaluation of aumdubin's impact on Bax protein ubiquitination and mitochondrial localization.
  • Investigation of USP30 inhibition's role in aumdubin-induced apoptosis.

Main Results:

  • Aumdubin demonstrated superior DUB-inhibiting and apoptosis-inducing effects compared to auranofin in lung cancer cells.
  • Aumdubin exhibits high affinity for the mitochondrial DUB USP30.
  • Aumdubin treatment led to increased ubiquitination and mitochondrial translocation of Bax protein.
  • Inhibition of USP30 was found to contribute to aumdubin-induced Bax-dependent apoptosis.

Conclusions:

  • The gold(I)-containing agent aumdubin induces Bax-dependent apoptosis in lung cancer cells.
  • Aumdubin's mechanism involves partial inhibition of the mitochondrial DUB USP30.
  • Aumdubin represents a promising therapeutic strategy for lung cancer, potentially via targeting USP30.

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