Description: <b>Methionine (MET) restriction (MR)</b> has been shown to arrest cancer growth and sensitizes tumors to chemotherapy. <br>
-Many cancer cells rely heavily on exogenous methionine to sustain rapid growth and proliferation because they often have impaired methionine salvage pathways.<br>
-Methionine contributes to the synthesis of glutathione, a key antioxidant. (Methionine is a precursor of glutathione, a tripeptide that reduces reactive oxygen species.)<br>
-MR diets might influence the redox state of cancer cells, increasing oxidative stress and thereby leading to cell death in metabolically compromised tumor cells.<br>
-Proliferation and growth of several types of cancer cells are inhibited by MR, while normal cells are unaffected by limiting methionine as long as homocysteine is present.<br>
-Methionine restriction is effective when the non-essential amino acid, cysteine, is absent from the diet or media. methionine is the precursor for cysteine which is essential for the formation of GSH.<br>
-Malignant cells lack the enzyme required to recycle homocysteine therefore giving methionine restriction the capacity to alter cancer cells while maintaining normal, healthy cells. <br>
<br>
While vegan diets are typically low in methionine, some nuts and legumes (such as Brazil nuts and kidney beans) are rich in methionine.<br>
<br>
Foods to avoid for MR diet:<br>
Animal Proteins: <br>
-Red Meat (Beef, Pork, Lamb):<br>
-Poultry (Chicken, Turkey): <br>
-Fish and Seafood: <br>
-Eggs: Both the egg whites and yolks are protein rich.<br>
-Dairy Products: Milk, cheese, and yogurt <br>
Certain Plant Proteins:<br>
-Soy Products:<br>
-Legumes: <br>
Protein Supplements:<br>
<br>
Foods Lower in Methionine (Often Favorable on an MR Diet)<br>
Fruits & Vegetables: leafy greens, berries, apples, and citrus fruits.<br>
Grains & Cereals: rice, oats, and barley <br>
Nuts and Seeds: can vary in methionine content. <br>
Alternative Protein Sources: emphasize protein sources with a lower methionine-to-cysteine ratio.<br>
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<table border="1" cellspacing="0" cellpadding="4">
<tr>
<th>Rank</th>
<th>Pathway / Target Axis</th>
<th>Direction</th>
<th>Primary Effect</th>
<th>Notes / Cancer Relevance</th>
<th>Ref</th>
</tr>
<tr>
<td>1</td>
<td>One-carbon metabolism (methionine cycle → folate cycle coupling)</td>
<td>↓ one-carbon flux (Met/SAM-linked metabolites)</td>
<td>Core metabolic constraint</td>
<td>Nature study shows dietary MR produces controlled, reproducible changes to one-carbon metabolism that alter cancer outcomes</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/31367041/">(ref)</a></td>
</tr>
<tr>
<td>2</td>
<td>Nucleotide biosynthesis (purines/thymidylate via one-carbon units)</td>
<td>↓ nucleotide synthesis capacity</td>
<td>DNA/RNA synthesis limitation</td>
<td>Same MR Nature paper links MR-driven one-carbon changes to pathways needed for proliferation and therapy response</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/31367041/">(ref)</a></td>
</tr>
<tr>
<td>3</td>
<td>Therapy sensitivity (chemo / targeted one-carbon therapy synergy)</td>
<td>↑ sensitivity / ↑ efficacy</td>
<td>Therapeutic potentiation</td>
<td>Dietary MR influences outcomes and can enhance responses to standard therapies through one-carbon metabolic rewiring</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/31367041/">(ref)</a></td>
</tr>
<tr>
<td>4</td>
<td>mTORC1 nutrient sensing (Met/SAM → SAMTOR mechanism)</td>
<td>↓ mTORC1 signaling when Met/SAM low</td>
<td>Reduced anabolic growth signaling</td>
<td>Mechanistic review: SAMTOR senses SAM (derived from methionine) and, when SAM is low, inhibits mTORC1 signaling</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/32850834/">(ref)</a></td>
</tr>
<tr>
<td>5</td>
<td>Integrated Stress Response (ISR; ATF4 induction under MR)</td>
<td>↑ ISR / ↑ ATF4</td>
<td>Amino-acid stress adaptation</td>
<td>MR activates ISR in TNBC cells (eIF2α phosphorylation; ATF4 and targets up), demonstrating stress signaling engagement under methionine restriction</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC6726988/">(ref)</a></td>
</tr>
<tr>
<td>6</td>
<td>Glutathione (GSH) / ferroptosis coupling (CHAC1 axis)</td>
<td>↑ CHAC1 / ↓ GSH / ↑ ferroptosis (context-dependent)</td>
<td>Redox vulnerability</td>
<td>Intermittent dietary methionine deprivation augments tumoral ferroptosis; paper links effect to CHAC1 upregulation (CHAC1 promotes GSH degradation)</td>
<td><a href="https://www.nature.com/articles/s41467-023-40518-0">(ref)</a></td>
</tr>
<tr>
<td>7</td>
<td>Epigenetic methylation capacity (SAM-dependent methylation)</td>
<td>↓ methylation potential (via ↓ SAM availability)</td>
<td>Altered gene regulation</td>
<td>Review focused on dietary methionine and cancer: MR impacts SAM-dependent methylation processes central to biosynthesis/regulation in tumors</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC6951023/">(ref)</a></td>
</tr>
<tr>
<td>8</td>
<td>Systemic growth signaling (IGF-1)</td>
<td>↓ IGF-1</td>
<td>Lower systemic pro-growth cue</td>
<td>Intermittent MR reduces circulating IGF-1 (healthspan paper, but the endocrine direction is explicit and relevant to tumor growth biology)</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/35570387/">(ref)</a></td>
</tr>
<tr>
<td>9</td>
<td>Radiation sensitization (clinical feasibility context)</td>
<td>↑ RT sensitivity (preclinical); feasible in humans</td>
<td>Translational evidence</td>
<td>Phase I pilot: MR diet given concurrently with radiation—supports feasibility/safety; paper states preclinical evidence of MRD sensitizing cancer to RT</td>
<td><a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC11407292/">(ref)</a></td>
</tr>
<tr>
<td>10</td>
<td>In vivo tumor growth</td>
<td>↓ tumor growth / ↓ progression (model-dependent)</td>
<td>Demonstrated anti-tumor effect</td>
<td>Nature MR paper demonstrates MR can influence tumor outcomes in mouse cancer models</td>
<td><a href="https://pubmed.ncbi.nlm.nih.gov/31367041/">(ref)</a></td>
</tr>
</table>