2. Academic Validation
  3. A G-quadruplex-binding platinum complex induces cancer mitochondrial dysfunction through dual-targeting mitochondrial and nuclear G4 enriched genome

A G-quadruplex-binding platinum complex induces cancer mitochondrial dysfunction through dual-targeting mitochondrial and nuclear G4 enriched genome

  • J Biomed Sci. 2024 May 13;31(1):50. doi: 10.1186/s12929-024-01041-6.
Keli Kuang # 1,  Chunyan Li # 1,  Fatlinda Maksut 2 3,  Deepanjan Ghosh 2 3,  Robin Vinck 4,  Maolin Wang 1,  Joël Poupon 5,  Run Xiang 6,  Wen Li 7,  Fei Li 1,  Zhu Wang 1,  Junrong Du 1,  Marie-Paule Teulade-Fichou 2 3,  Gilles Gasser 4,  Sophie Bombard 8 9,  Tao Jia 10 11 12
Affiliations

Affiliations

  • 1 Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, 610041, Chengdu, China.
  • 2 CNRS-UMR9187, INSERM U1196, PSL-Research University, 91405, Orsay, France.
  • 3 CNRS-UMR9187, INSERM U1196, Université Paris Saclay, 91405, Orsay, France.
  • 4 Chimie ParisTech, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, PSL University, CNRS, F-75005, Paris, France.
  • 5 Hôpital Lariboisière (AP-HP), Laboratoire de Toxicologie Biologique, 2 rue Ambroise Paré, 75475, Paris, France.
  • 6 Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China.
  • 7 Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
  • 8 CNRS-UMR9187, INSERM U1196, PSL-Research University, 91405, Orsay, France. Sophie.bombard@curie.fr.
  • 9 CNRS-UMR9187, INSERM U1196, Université Paris Saclay, 91405, Orsay, France. Sophie.bombard@curie.fr.
  • 10 Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, 610041, Chengdu, China. taojia86@scu.edu.cn.
  • 11 CNRS-UMR9187, INSERM U1196, PSL-Research University, 91405, Orsay, France. taojia86@scu.edu.cn.
  • 12 CNRS-UMR9187, INSERM U1196, Université Paris Saclay, 91405, Orsay, France. taojia86@scu.edu.cn.
  • # Contributed equally.
PMID: 38741159 DOI: 10.1186/s12929-024-01041-6
Abstract

Background: G-quadruplex DNA (G4) is a non-canonical structure forming in guanine-rich regions, which play a vital role in Cancer biology and are now being acknowledged in both nuclear and mitochondrial (mt) genome. However, the impact of G4-based targeted therapy on both nuclear and mt genome, affecting mt function and its underlying mechanisms remain largely unexplored.

Methods: The mechanisms of action and therapeutic effects of a G4-binding platinum(II) complex, Pt-ttpy, on mitochondria were conducted through a comprehensive approaches with in vitro and in vivo models, including ICP-MS for platinum measurement, PCR-based genetic analysis, western blotting (WB), confocal microscope for mt morphology study, extracellular flux analyzer, JC1 and Annexin V Apoptosis assay, flow cytometry and high content microscope screening with single-cell quantification of both ROS and mt specific ROS, as well as click-chemistry for IF study of mt translation. Decipher Pt-ttpy effects on nuclear-encoded mt related genes expression were undertaken via RNA-seq, Chip-seq and CUT-RUN assays.

Results: Pt-ttpy, shows a highest accumulation in the mitochondria of A2780 Cancer cells as compared with two Other platinum(II) complexes with no/weak G4-binding properties, Pt-tpy and cisplatin. Pt-ttpy induces mtDNA deletion, copy reduction and transcription inhibition, hindering mt protein translation. Functional analysis reveals potent mt dysfunction without Reactive Oxygen Species (ROS) induction. Mechanistic study provided first evidence that most of mt ribosome genes are highly enriched in G4 structures in their promoter regions, notably, Pt-ttpy impairs most nuclear-encoded mt ribosome genes' transcription through dampening the recruiting of transcription initiation and elongation factors of NELFB and TAF1 to their promoter with G4-enriched sequences. In vivo studies show Pt-ttpy's efficient anti-tumor effects, disrupting mt genome function with fewer side effects than cisplatin.

Conclusion: This study underscores Pt-ttpy as a G4-binding platinum(II) complex, effectively targeting Cancer mitochondria through dual action on mt and nuclear G4-enriched genomes without inducing ROS, offering promise for safer and effective platinum-based G4-targeted Cancer therapy.

Keywords

Chemotherapy; G4; Mito-Nuclear interactions; Mitochondrial genome; Platinum complex; ROS.

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