Differences in cell death in methionine versus cysteine depletion

Area of Science:

• Biochemistry
• Oncology
• Cell Biology

Background:

• Sulfur amino acid restriction (methionine, cysteine) is explored as cancer adjuvant therapy.
• Cysteine depletion is linked to ferroptosis; methionine depletion's role is less understood.

Purpose of the Study:

• Compare melanoma cell responses to methionine vs. cysteine depletion.
• Investigate the distinct roles of methionine and cysteine in cancer cell fate.

Main Methods:

• Analyzed melanoma cell responses to methionine depletion, methionine replacement with homocysteine, and cysteine depletion.
• Assessed gene expression, transcription factor activation (ATF4, NRF2), glutathione levels, and lipid peroxidation.

Main Results:

• All conditions induced ATF4; methionine replacement with homocysteine triggered a ferroptotic gene signature.
• Methionine and cysteine depletion activated the NRF2 antioxidant pathway.
• Cysteine depletion caused a 95% glutathione decrease and increased lipid peroxidation, inducing ferroptosis.
• Methionine depletion caused a 42% glutathione decrease and induced apoptosis, not ferroptosis.

Conclusions:

• Methionine restriction and cysteine depletion induce distinct cell death pathways (apoptosis vs. ferroptosis) despite overlapping gene expression.
• A strong ATF4-driven ferroptotic signature requires profound glutathione depletion to induce ferroptosis.
• Differential responses highlight potential for targeted sulfur amino acid-based cancer therapies.