GABA(A) Receptor Activation Drives GABARAP-Nix Mediated Autophagy to Radiation-Sensitize Primary and Brain-Metastatic Lung Adenocarcinoma Tumors.

Autor: Bhattacharya D; Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA., Barrile R; Department of Biomedical Engineering, University of Cincinnati, Cincinnati, OH 45221, USA., Toukam DK; Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA., Gawali VS; Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA., Kallay L; Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA., Ahmed T; Department of Chemistry and Biochemistry, Milwaukee Institute of Drug Discovery, University of Wisconsin, Milwaukee, WI 53211, USA., Brown H; Department of Chemistry, Tufts University, Medford, MA 02144, USA., Rezvanian S; Department of Chemistry and Biochemistry, Milwaukee Institute of Drug Discovery, University of Wisconsin, Milwaukee, WI 53211, USA., Karve A; Division of Pharmaceutical Sciences, University of Cincinnati College of Pharmacy, Cincinnati, OH 45229, USA., Desai PB; Division of Pharmaceutical Sciences, University of Cincinnati College of Pharmacy, Cincinnati, OH 45229, USA., Medvedovic M; Department of Environmental & Public Health Sciences, University of Cincinnati, Cincinnati, OH 45267, USA., Wang K; Department of Radiation Oncology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA., Ionascu D; Department of Radiation Oncology, University of Cincinnati College of Medicine, Cincinnati, OH 45219, USA., Harun N; Division of Biostatistics & Epidemiology, Cincinnati Children's Hospital, Cincinnati, OH 45229, USA., Vallabhapurapu S; Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA., Wang C; Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA., Qi X; Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA., Baschnagel AM; Department of Human Oncology, University of Wisconsin, Madison, WI 53792, USA., Kritzer JA; Department of Chemistry, Tufts University, Medford, MA 02144, USA., Cook JM; Department of Chemistry and Biochemistry, Milwaukee Institute of Drug Discovery, University of Wisconsin, Milwaukee, WI 53211, USA., Pomeranz Krummel DA; Department of Neurosurgery, University of North Carolina, Chapel Hill, NC 27599, USA.; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA., Sengupta S; Department of Neurosurgery, University of North Carolina, Chapel Hill, NC 27599, USA.; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.; Department of Neurology, University of North Carolina, Chapel Hill, NC 27517, USA.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2024 Sep 15; Vol. 16 (18). Date of Electronic Publication: 2024 Sep 15.
DOI: 10.3390/cancers16183167
Abstrakt: In non-small cell lung cancer (NSCLC) treatment, radiotherapy responses are not durable and toxicity limits therapy. We find that AM-101, a synthetic benzodiazepine activator of GABA(A) receptor, impairs the viability and clonogenicity of both primary and brain-metastatic NSCLC cells. Employing a human-relevant ex vivo 'chip', AM-101 is as efficacious as docetaxel, a chemotherapeutic used with radiotherapy for advanced-stage NSCLC. In vivo, AM-101 potentiates radiation, including conferring a significant survival benefit to mice bearing NSCLC intracranial tumors generated using a patient-derived metastatic line. GABA(A) receptor activation stimulates a selective-autophagic response via the multimerization of GABA(A) receptor-associated protein, GABARAP, the stabilization of mitochondrial receptor Nix, and the utilization of ubiquitin-binding protein p62. A high-affinity peptide disrupting Nix binding to GABARAP inhibits AM-101 cytotoxicity. This supports a model of GABA(A) receptor activation driving a GABARAP-Nix multimerization axis that triggers autophagy. In patients receiving radiotherapy, GABA(A) receptor activation may improve tumor control while allowing radiation dose de-intensification to reduce toxicity.
Databáze: MEDLINE