Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitochondrial topoisomerase IB (TOP1MT) is a nuclear-encoded topoisomerase, exclusively localized to mitochondria, which resolves topological stress generated during mtDNA replication and transcription. Here, we report that TOP1MT is overexpressed in cancer tissues and demonstrate that TOP1MT deficiency attenuates tumor growth in human and mouse models of colon and liver cancer. Due to their mitochondrial dysfunction, TOP1MT-KO cells become addicted to glycolysis, which limits synthetic building blocks and energy supply required for the proliferation of cancer cells in a nutrient-deprived tumor microenvironment. Mechanistically, we show that TOP1MT associates with mitoribosomal subunits, ensuring optimal mitochondrial translation and assembly of oxidative phosphorylation complexes that are critical for sustaining tumor growth. The TOP1MT genomic signature profile, based on Top1mt-KO liver cancers, is correlated with enhanced survival of hepatocellular carcinoma patients. Our results highlight the importance of TOP1MT for tumor development, providing a potential rationale to develop TOP1MT-targeted drugs as anticancer therapies.
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PMID:The mitochondrial type IB topoisomerase drives mitochondrial translation and carcinogenesis. 3062 57

Mitochondria contain their own genome (mtDNA), encoding 13 proteins of the enzyme complexes of the oxidative phosphorylation. Synthesis of these 13 mitochondrial proteins requires a specific translation machinery, the mitoribosomes whose RNA components are encoded by the mtDNA, whereas more than 80 proteins are encoded by nuclear genes. It has been well established that mitochondrial topoisomerase I (TOP1MT) is important for mtDNA integrity and mitochondrial transcription as it prevents excessive mtDNA negative supercoiling and releases topological stress during mtDNA replication and transcription. We recently showed that TOP1MT also supports mitochondrial protein synthesis, and thus is critical for promoting tumor growth. Impaired mitochondrial protein synthesis leads to activation of the mitonuclear stress response through the transcription factor ATF4, and induces cytoprotective genes in order to prevent mitochondrial and cellular dysfunction. In this perspective, we highlight the novel role of TOP1MT in mitochondrial protein synthesis and as potential target for chemotherapy.
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PMID:Beyond the unwinding: role of TOP1MT in mitochondrial translation. 3134 95