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Related Concept Videos

Improving Translational Accuracy02:07

Improving Translational Accuracy

Base complementarity between the three base pairs of mRNA codon and the tRNA anticodon is not a failsafe mechanism. Inaccuracies can range from a single mismatch to no correct base pairing at all. The free energy difference between the correct and nearly correct base pairs can be as small as 3 kcal/ mol. With complementarity being the only proofreading step, the estimated error frequency would be one wrong amino acid in every 100 amino acids incorporated. However, error frequencies observed in...
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During most eukaryotic translation processes, the small 40S ribosome subunit scans an mRNA from its 5' end until it encounters the first start AUG codon. The large 60S ribosomal subunit then joins the smaller one to initiate protein synthesis. The location of the translation initiation is largely determined by the nucleotides near the start codon as there may be multiple translation initiation sites present on the mRNA.  Marilyn Kozak discovered that the sequence RCCAUGG (where R stands for...
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Analysis of Translation Initiation During Stress Conditions by Polysome Profiling
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Ribosome Profiling Reveals Translational Reprogramming via mTOR Activation in Omacetaxine-Resistant Multiple Myeloma.

Zachary J Walker1, Katherine F Vaeth2,3, Amber Baldwin2,3

  • 1Division of Hematology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Molecular Cancer Research : MCR
|March 6, 2025
PubMed
Summary
This summary is machine-generated.

Multiple myeloma cells are sensitive to the translation inhibitor omacetaxine. Combining omacetaxine with mTOR inhibitors overcomes resistance and shows promise for treating multiple myeloma.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Protein homeostasis is crucial for multiple myeloma (MM) cell survival.
  • Proteasome inhibitors target MM, but mRNA translation inhibition is an underexplored therapeutic strategy.
  • MM cells exhibit sensitivity to the translation inhibitor omacetaxine.

Purpose of the Study:

  • To investigate mechanisms of omacetaxine resistance in multiple myeloma.
  • To identify potential drug combinations to prevent or delay relapse in MM.
  • To evaluate the efficacy of combining omacetaxine with mTOR inhibitors.

Main Methods:

  • Generated omacetaxine-resistant MM cell lines (H929, MM1S).
  • Utilized RNA-sequencing and ribosome profiling (Ribo-seq) to analyze gene expression and translation.
  • Assessed the effects of mTOR inhibition (Torin 1) on omacetaxine sensitivity in vitro and in vivo.

Main Results:

  • Resistant MM cells showed significantly decreased sensitivity to omacetaxine (EC50 > 100 nM vs. 24-54 nM).
  • Upregulation of translation factors and TOP motif-containing mRNAs was observed in resistant cells.
  • mTOR inhibition restored partial omacetaxine sensitivity in resistant cells and demonstrated synergistic effects in naïve cells and in vivo.

Conclusions:

  • mTOR pathway activation contributes to omacetaxine resistance in multiple myeloma.
  • Combining omacetaxine with mTOR inhibitors is a rational and effective strategy for MM treatment.
  • This combination therapy shows promise for overcoming resistance and improving outcomes in patients with multiple myeloma.