Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability

Area of Science:

• Molecular Biology
• Cancer Research
• Biochemistry

Background:

• Glutathione peroxidase 4 (GPX4) is a key selenoprotein that prevents ferroptosis by neutralizing lipid peroxides.
• GPX4 inhibition is a cancer treatment strategy, but resistance mechanisms limit its efficacy.
• Understanding ferroptosis resistance is crucial for developing effective cancer therapies.

Purpose of the Study:

• To identify novel factors contributing to cancer cell ferroptosis resistance.
• To elucidate the molecular mechanisms underlying GPX4 inhibition resistance in cancer.
• To uncover potential therapeutic vulnerabilities associated with ferroptosis resistance.

Main Methods:

• Chemical-genetic screening to identify ferroptosis resistance factors.
• Analysis of LRP8 expression and its impact on cellular selenium and selenoprotein levels.
• Investigation of GPX4 translation efficiency, ribosome dynamics, and protein degradation pathways.

Main Results:

• LRP8 (ApoER2) was identified as a ferroptosis resistance factor upregulated in cancer.
• Loss of LRP8 reduced cellular selenium, leading to decreased GPX4 expression via impaired translation.
• Ribosome stalling and collisions at the GPX4 selenocysteine codon caused translation termination and proteasomal degradation.

Conclusions:

• Cancer cells exhibit a rewired selenoprotein hierarchy, with LRP8 influencing GPX4 levels.
• Impaired GPX4 translation due to ribosome stalling presents a novel ferroptosis vulnerability in cancer.
• Targeting LRP8 or overcoming translation defects could enhance ferroptosis-based cancer treatments.