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Updated: Sep 15, 2025

Author Spotlight: Transmitochondrial Cybrid Generation Using Cancer Cell Lines
Published on: March 17, 2023
Mitochondrial Translation Inhibition Uncovers a Critical Metabolic-Epigenetic Interface in Renal Cell Carcinoma
Kazumi Eckenstein1, Beyza Cengiz1, Matthew E K Chang2
1Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97201, USA.
Background/Objectives:
Renal cell carcinoma (RCC) exhibits distinctive metabolic vulnerabilities that may be therapeutically targeted. This study investigates how tigecycline, an FDA-approved antibiotic that inhibits mitochondrial translation, affects RCC cells and explores potential combinatorial approaches to enhance its efficacy.
Methods:
We employed comprehensive metabolomic profiling, subcellular proteomics, and functional assays to characterize the effects of tigecycline on RCC cell lines, patient-derived organoids, and xenograft models. The synergistic potential of tigecycline with the histone deacetylase inhibitor entinostat was evaluated using combination index analysis.
Results:
Tigecycline selectively inhibited mitochondrial translation in RCC cells, reducing mitochondrially-encoded proteins while sparing nuclear-encoded components, profoundly disrupting mitochondrial bioenergetics and reducing tumor growth in xenograft models. Subcellular proteomic analyses revealed that tigecycline treatment triggered significant accumulation of multiple histone variants concurrent with cell cycle arrest. Based on this discovery, combined treatment with tigecycline and entinostat demonstrated remarkable synergism across RCC cell lines and patient derived organoids.
Conclusions:
Our findings identify a promising therapeutic opportunity by targeting the crosstalk between mitochondrial function and epigenetic homeostasis in RCC, with potential for rapid clinical translation given the established pharmacological profiles of both agents.
Insights
Tigecycline targets mitochondrial translation in renal cell carcinoma (RCC), reducing tumor growth. Combining tigecycline with entinostat shows significant synergy, offering a new therapeutic strategy for RCC.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Renal cell carcinoma (RCC) presents unique metabolic vulnerabilities.
- Targeting these vulnerabilities offers therapeutic potential.
Purpose of the Study:
- Investigate tigecycline's effect on RCC cells.
- Explore combinatorial therapies to enhance tigecycline efficacy.
Main Methods:
- Utilized metabolomic profiling, subcellular proteomics, and functional assays.
- Assessed tigecycline effects in RCC cell lines, organoids, and xenografts.
- Evaluated tigecycline and entinostat synergy.
Main Results:
- Tigecycline inhibited mitochondrial translation and reduced RCC tumor growth.
- Tigecycline induced histone variant accumulation and cell cycle arrest.
- Combined tigecycline and entinostat demonstrated significant synergism.
Conclusions:
- Targeting mitochondrial-epigenetic crosstalk is a promising RCC strategy.
- Combination therapy holds potential for clinical translation.
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