ArticleEMBO reports2022
Metabolic resistance to the inhibition of mitochondrial transcription revealed by CRISPR-Cas9 screen.
Article in EMBO reports, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed.
- Mitochondria-Targeted Nanotherapies in Aging Neurodegenerative Disorders: Emerging Prospects and Clinical Potential.Advanced healthcare materials · 2026Review
- SLIRP maintains energy metabolism homeostasis in colorectal cancer by stabilizing mitochondrial-encoded mRNAs.British journal of cancer · 2026Article
- Inducible CRISPR/Cas systems in precision oncology: Current applications and future perspectives.Clinical and translational medicine · 2026Review
- Re-evaluating the rationale for targeting oxidative phosphorylation in acute myeloid leukemia.The Biochemical journal · 2026Review
- Deregulation of mitochondrial gene expression in cancer: mechanisms and therapeutic opportunities.British journal of cancer · 2024Review
- Targeting POLRMT by IMT1 inhibits colorectal cancer cell growth.Cell death & disease · 2024Article
- HOXC11-mediated regulation of mitochondrial function modulates chemoresistance in colorectal cancer.BMC cancer · 2024Article
- Identification of the central role of RNA polymerase mitochondrial for angiogenesis.Cell communication and signaling : CCS · 2024Article
- A kinetic dichotomy between mitochondrial and nuclear gene expression processes.Molecular cell · 2024Article
- CRISPR-Cas9 applications in T cells and adoptive T cell therapies.Cellular & molecular biology letters · 2024Review
- An Update on the Application of CRISPR Technology in Clinical Practice.Molecular biotechnology · 2024Review
- Targeting POLRMT by a first-in-class inhibitor IMT1 inhibits osteosarcoma cell growth in vitro and in vivo.Cell death & disease · 2024Article
- Protective Role of MAVS Signaling for Murine Lipopolysaccharide-Induced Acute Kidney Injury.ImmunoHorizons · 2024Article
- Mitochondrial nucleic acids in innate immunity and beyond.Experimental & molecular medicine · 2023Review
- Exploring Molecular Targets for Mitochondrial Therapies in Neurodegenerative Diseases.International journal of molecular sciences · 2023Review
- Targeting Mitochondrial DNA Transcription by POLRMT Inhibition or Depletion as a Potential Strategy for Cancer Treatment.Biomedicines · 2023Review
- A first-in-class POLRMT specific inhibitor IMT1 suppresses endometrial carcinoma cell growth.Cell death & disease · 2023Article
- Ten Years of CRISPRing Cancers In Vitro.Cancers · 2022Review
- Mitochondrial DNA mutations in ageing and cancer.Molecular oncology · 2022Review
- The mitochondrial RNA polymerase POLRMT promotes skin squamous cell carcinoma cell growth.Cell death discovery · 2022Article
Corrections and comments
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Authors and funding
7 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cancer cells depend on mitochondria to sustain their increased metabolic need and mitochondria therefore constitute possible targets for cancer treatment. We recently developed small-molecule inhibitors of mitochondrial transcription (IMTs) that selectively impair mitochondrial gene expression. IMTs have potent antitumor properties in vitro and in vivo, without affecting normal tissues. Because therapy-induced resistance is a major constraint to successful cancer therapy, we investigated mechanisms conferring resistance to IMTs. We employed a CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats)-(CRISP-associated protein 9) whole-genome screen to determine pathways conferring resistance to acute IMT1 treatment. Loss of genes belonging to von Hippel-Lindau (VHL) and mammalian target of rapamycin complex 1 (mTORC1) pathways caused resistance to acute IMT1 treatment and the relevance of these pathways was confirmed by chemical modulation. We also generated cells resistant to chronic IMT treatment to understand responses to persistent mitochondrial gene expression impairment. We report that IMT1-acquired resistance occurs through a compensatory increase of mitochondrial DNA (mtDNA) expression and cellular metabolites. We found that mitochondrial transcription factor A (TFAM) downregulation and inhibition of mitochondrial translation impaired survival of resistant cells. The identified susceptibility and resistance mechanisms to IMTs may be relevant for different types of mitochondria-targeted therapies.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.