SIRT5 Activation and Inorganic Phosphate Binding Reduce Cancer Cell Vitality by Modulating Autophagy/Mitophagy and...

Area of Science:

• Oncology
• Biochemistry
• Cell Biology

Background:

• Cancer cells exhibit heightened glutamine metabolism, a process critical for their growth.
• Glutaminase (GLS) is a key enzyme in glutamine catabolism, often overexpressed in breast tumors, particularly triple-negative subtypes.
• Sirtuin 5 (SIRT5) has been identified as an inhibitor of GLS activity and ammonia production.

Purpose of the Study:

• To investigate the potential of activating SIRT5 and reducing inorganic phosphate (Pi) as an anticancer strategy.
• To explore the combined effects of a novel SIRT5 activator (MC3138) and a Pi chelator (lanthanum acetate) on cancer cell proliferation.

Main Methods:

• Treatment of cancer cells with MC3138, a selective SIRT5 activator.
• Co-treatment with lanthanum acetate, an inorganic phosphate chelator.
• Assessment of cell viability, clonogenicity, autophagy markers (MAP1LC3B, ULK1), mitophagy markers (BNIP3), and reactive oxygen species (ROS) levels.

Main Results:

• MC3138 treatment mimicked SIRT5 overexpression effects, inhibiting GLS activity.
• Combined treatment with MC3138 and lanthanum acetate significantly reduced cancer cell viability and clonogenicity.
• Modulation of autophagy and mitophagy pathways, alongside increased ROS levels, was observed.

Conclusions:

• SIRT5 activation and/or Pi reduction represent a viable strategy to inhibit cancer cell proliferation.
• The combined approach effectively reduces glutamine metabolism and alters mitophagy.
• This leads to a detrimental accumulation of reactive oxygen species (ROS), promoting cell death.