PPT1 regulates mitochondrial redox by depalmitoylating PRDX3.

Area of Science:

• Hematology
• Oncology
• Biochemistry
• Cell Biology

Background:

• Multiple myeloma (MM) is an incurable hematological cancer characterized by enhanced antioxidant capacity.
• Peroxiredoxins (PRDXs) are overexpressed in MM, correlating with poor prognosis, but their regulation remains unclear.
• Understanding PRDX regulation is crucial for developing novel MM therapies.

Purpose of the Study:

• To identify novel therapeutic targets in MM by investigating PRDX regulation.
• To elucidate the role of PPT1 in MM pathogenesis and its relationship with PRDX3.
• To evaluate PPT1 as a potential therapeutic target for MM.

Main Methods:

• Investigated the enzymatic activity of PPT1 on PRDX3, focusing on depalmitoylation at C108.
• Utilized genetic and chemical inhibition of PPT1 in MM cell lines.
• Assessed the impact of PPT1 inhibition on cell viability, mitochondrial reactive oxygen species (mtROS) levels, and PRDX3 S-palmitoylation.
• Evaluated the efficacy of PPT1 inhibition in MM xenograft tumor models.

Main Results:

• PPT1 was identified as the enzyme catalyzing PRDX3 depalmitoylation at C108.
• Inhibition of PPT1 induced significant cytotoxicity in MM cells.
• PPT1 inhibition led to elevated mtROS levels and increased PRDX3 S-palmitoylation.
• PPT1 inhibition suppressed xenograft tumor growth in vivo.

Conclusions:

• PPT1 is the bona fide depalmitoylase of PRDX3, sustaining its antioxidant activity.
• The PPT1-PRDX3 axis represents a promising therapeutic target for multiple myeloma.
• Targeting PPT1 offers a novel strategy to combat MM by disrupting redox homeostasis and inducing cancer cell death.