GABA(A) Receptor Activation Drives GABARAP–Nix Mediated Autophagy to Radiation-Sensitize Primary and Brain-Metastatic Lung Adenocarcinoma Tumors
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.
Authors
- Soma Sengupta (ORCID: https://orcid.org/0000-0003-4577-1397)
- Riccardo Barrile (ORCID: https://orcid.org/0000-0002-7301-3959)
- Sepideh Rezvanian
- Mario Medvedovic
- Subrahmanya Vallabhapurapu
- Aniruddha S. Karve (ORCID: https://orcid.org/0000-0002-1617-4828)
- Hawley Brown (ORCID: https://orcid.org/0009-0001-9855-5877)
- Xiaoyang Qi (ORCID: https://orcid.org/0000-0001-5363-1760)
- James M. Cook (ORCID: https://orcid.org/0000-0001-5512-3022)
- Dan Ionascu (ORCID: https://orcid.org/0000-0002-2307-7794)
- Chenran Wang (ORCID: https://orcid.org/0000-0003-4181-2729)
- Vaibhavkumar S. Gawali (ORCID: https://orcid.org/0000-0002-7917-4913)
- Joshua A. Kritzer (ORCID: https://orcid.org/0000-0003-2878-6781)
- Kyle Wang (ORCID: https://orcid.org/0000-0002-8374-021X)
- Pankaj B. Desai (ORCID: https://orcid.org/0000-0002-3001-1603)
- Donatien Kamdem Toukam (ORCID: https://orcid.org/0009-0004-2653-7700)
- Nusrat Harun (ORCID: https://orcid.org/0000-0002-0802-3413)
- Taukir Ahmed
- Debanjan Bhattacharya (ORCID: https://orcid.org/0000-0001-5887-805X)
- Laura Kallay (ORCID: https://orcid.org/0000-0003-4117-2549)
- Daniel A. Pomeranz Krummel
Institutions
- University of North Carolina at Chapel Hill (US)
- Tufts University (US)
- Cincinnati Children's Hospital Medical Center (US)
- University of Wisconsin–Madison (US)
- University of Wisconsin–Milwaukee (US)
- UNC Lineberger Comprehensive Cancer Center
- University of Cincinnati (US)
- University of Cincinnati Medical Center (US)
Publication Details
- Journal
- Cancers
- Published
- 2024-09-15
- DOI
- https://doi.org/10.3390/cancers16183167
- Citations
- 8
- Primary Topic
- Autophagy in Disease and Therapy
- Type
- article
- Field-Weighted Citation Impact
- 3.09
Funders
- University of Cincinnati