Naphthoquinone-induced arylation inhibits Sirtuin 7 activity

Area of Science:

• Biochemistry
• Molecular Biology
• Cell Biology

Background:

• Naphthoquinones possess anticancer properties by generating reactive oxygen species and reacting with cellular nucleophiles.
• Understanding the precise molecular mechanisms of naphthoquinones is crucial for developing effective cancer therapies.

Purpose of the Study:

• To investigate the molecular mechanism of action of naphthoquinones, specifically menadione and plumbagin, in human HeLa cells.
• To determine the effect of menadione and plumbagin on the nucleolar NAD+-dependent deacetylase Sirtuin 7 (SIRT7).

Main Methods:

• In vitro and in vivo assays were used to assess the inhibition of SIRT7 catalytic activity by menadione and plumbagin.
• Ribosomal DNA (rDNA) transcription and pre-ribosomal RNA (pre-rRNA) processing were measured to evaluate SIRT7 inhibition.
• The role of thiol arylation in SIRT7 inhibition was investigated using N-acetyl-L-cysteine.

Main Results:

• Menadione and plumbagin were found to inhibit SIRT7 activity both in vitro and in vivo.
• Inhibition of SIRT7 activity correlated with reduced rDNA transcription and pre-rRNA processing.
• Preventing sulfhydryl arylation with N-acetyl-L-cysteine blocked the inhibitory effect of menadione and plumbagin on SIRT7.

Conclusions:

• Menadione and plumbagin inhibit SIRT7 catalytic activity, likely through covalent modification of thiol groups.
• SIRT7 inhibition by these naphthoquinones may be a critical mechanism underlying their anticancer properties.
• Targeting SIRT7 could be a valuable strategy for combination cancer therapy.