Reversible Nucleolar Stress and Cell Growth Arrest Triggered by Acidic pH.

Area of Science:

• Cell Biology
• Cancer Biology
• Biochemistry

Background:

• The tumor microenvironment often features hypoxia and extracellular acidosis.
• Ribosome biogenesis is crucial for cell proliferation but sensitive to cellular stress, inducing nucleolar stress.
• The impact of extracellular acidosis on ribosome biogenesis and nucleolar stress is not well understood.

Purpose of the Study:

• To investigate whether extracellular acidosis impairs ribosome biogenesis and induces nucleolar stress in cancer cells.
• To elucidate the mechanisms underlying acidosis-induced nucleolar stress and its consequences on cell proliferation.
• To explore the potential of targeting this acidosis-driven stress response for cancer therapy.

Main Methods:

• Cancer cells were cultured under acidic conditions (pH 6.5).
• RNA sequencing was performed to analyze gene expression changes.
• Pre-ribosomal RNA (pre-rRNA) levels and nucleolar protein NPM1 localization were assessed.
• Cell cycle progression and proliferation were measured.
• Intracellular redox balance was evaluated, and the effect of antioxidants was tested.

Main Results:

• Acidic pH significantly downregulated ribosome biogenesis genes and reduced pre-rRNA levels.
• Acidic conditions induced nucleolar stress, characterized by NPM1 translocation and G1 phase arrest.
• The observed effects on ribosome biogenesis, NPM1 localization, and cell proliferation were reversible upon restoring neutral pH.
• Acidic pH induced an oxidized intracellular redox state, and dithiothreitol partially reversed NPM1 translocation.

Conclusions:

• Extracellular acidosis impairs ribosome biogenesis, leading to nucleolar stress and reversible growth inhibition in cancer cells.
• Oxidative stress partially contributes to the nucleolar stress response induced by acidosis.
• Acidosis-induced nucleolar stress represents a potential therapeutic vulnerability in solid tumors, offering novel strategies to combat treatment resistance.