Mitochondrial Translation Inhibition Uncovers a Critical Metabolic-Epigenetic Interface in Renal Cell Carcinoma
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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.
