The Mitochondrial Protease LonP1 Promotes Proteasome Inhibitor Resistance in Multiple Myeloma

Laure Maneix1,2,3,4, Melanie A Sweeney1,2,3,4, Sukyeong Lee5

  • 1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.

Cancers
|March 6, 2021
PubMed

Insights

Multiple myeloma cells develop resistance to proteasome inhibitors by increasing mitochondrial protease LonP1 activity. Targeting both proteasome and LonP1 may improve treatment for this incurable cancer.

Area of Science:

  • Biochemistry
  • Oncology
  • Molecular Biology

Background:

  • Multiple myeloma is an incurable cancer affecting 3% of the elderly population.
  • Proteasome inhibitors are crucial in treating multiple myeloma but often lead to drug resistance.
  • The mechanisms of relapsed/refractory multiple myeloma are complex and not fully understood.

Purpose of the Study:

  • To investigate the role of mitochondrial proteases in counterbalancing proteasome inhibitor efficacy.
  • To determine if mitochondrial proteases contribute to drug resistance in multiple myeloma.

Main Methods:

  • Analysis of clinical and experimental data.
  • Assessing the impact of LonP1 (Lon Peptidase 1) overexpression on proteasome inhibitor efficacy.
  • Evaluating the cross-inhibition of LonP1 by certain proteasome inhibitors.

Main Results:

  • Overexpression of mitochondrial matrix protease LonP1 reduces proteasome inhibitor efficacy.
  • LonP1 overexpression confers resistance even to proteasome inhibitors that do not inhibit LonP1.
  • LonP1 can compensate for proteasome activity loss.

Conclusions:

  • Mitochondrial proteases, specifically LonP1, play a significant role in multiple myeloma drug resistance.
  • Targeting both the proteasome and mitochondrial proteases like LonP1 could be a promising therapeutic strategy.

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