Leucine Deprivation and Chemotherapy Induce Aberrant Protein Production in Cancer
Author Information
Author(s): Kochavi Adva, Nagel Remco, Körner Pierre-Rene, Bleijerveld Onno B, Lin Chun-Pu, Huinen Zowi, Malka Yuval, Proost Natalie, van de Ven Marieke, Feng Xiaodong, Navarro Jasmine Montenegro, Pataskar Abhijeet, Peeper Daniel S, Champagne Julien, Agami Reuven
Primary Institution: The Netherlands Cancer Institute
Hypothesis
Leucine deprivation and chemotherapeutic agents lead to ribosomal stalling and aberrant protein production in cancer cells.
Conclusion
Leucine deprivation and DNA damage from chemotherapy induce aberrant protein production primarily at UUA codons, which can be targeted for anti-cancer therapy.
Supporting Evidence
- Leucine deprivation leads to ribosomal stalling at UUA codons.
- Chemotherapeutic agents induce similar effects on UUA codons.
- Faulty protein products can be presented as neoepitopes for T-cell recognition.
- Low levels of tRNALeu(UAA) restrict mRNA translation.
- SLFN11 activation during DNA damage leads to similar ribosomal stalling.
- UUA-derived aberrant peptides can elicit T-cell activation.
- Combination of chemotherapy and T-cell therapy shows potential for tumor growth impact.
Takeaway
When cancer cells don't have enough leucine, they make mistakes while making proteins, which can help the immune system recognize and attack them.
Methodology
The study involved ribosome profiling and flow cytometry to analyze protein production in cancer cells under leucine deprivation and DNA damage conditions.
Limitations
Leucine deprivation reduced HLA expression, potentially limiting peptide presentation for immune recognition.
Statistical Information
P-Value
p<0.001
Statistical Significance
p<0.001
Digital Object Identifier (DOI)
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