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Genome-wide CRISPR screen reveals CGS-15943 induced heme-dependent cell death mediated by aryl hydrocarbon receptor
Bach D Nguyen1,2,3, Siva K Kolluri4,5
1Cancer Research Laboratory, Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, OR, 97331, USA.
Abstract:
Induction of programmed cancer cell death by selective aryl hydrocarbon receptor (AHR) ligands represents a promising strategy for developing novel anticancer therapeutics. In this study, we characterized the anticancer activity and underlying mechanism of the selective AHR ligand CGS-15943 in lung cancer cells. CGS-15943 potently inhibited the growth of lung cancer cell lines expressing high levels of AHR, whereas CRISPR-mediated knockout of AHR in H460 and H69AR cells markedly rescued cells from CGS-15943-induced cell death, demonstrating an essential role for AHR. To identify additional mediators of this response, we performed a genome-wide CRISPR knockout screen, which revealed eight enzymes involved in the heme biosynthesis pathway, three heme-containing enzymes, as well as AHR and its transcriptional partner ARNT, as critical determinants of CGS-15943-induced cell death. Transcriptomic analyses further showed that CGS-15943 induced AHR-dependent transcriptional programs enriched for oxidative stress and oxidized phospholipid response pathways. Together, these findings identify key components of the AHR signaling network that regulate a programmed heme-dependent cell death pathway and establish CGS-15943 as a promising lead compound for targeting AHR-positive lung cancers.
Insights
Selective aryl hydrocarbon receptor (AHR) ligand CGS-15943 induces programmed cancer cell death in lung cancer. This AHR-dependent pathway involves heme biosynthesis and oxidative stress, highlighting CGS-15943 as a potential lung cancer therapeutic.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Selective aryl hydrocarbon receptor (AHR) ligands offer a promising therapeutic strategy for cancer by inducing programmed cell death.
- Understanding the precise mechanisms of AHR-mediated cell death is crucial for developing effective anticancer drugs.
Purpose of the Study:
- To investigate the anticancer activity and mechanism of the selective AHR ligand CGS-15943 in lung cancer cells.
- To identify key molecular players involved in AHR-dependent cell death induced by CGS-15943.
Main Methods:
- Utilized lung cancer cell lines with varying AHR expression levels.
- Employed CRISPR-mediated AHR knockout to assess AHR's role in cell death.
- Conducted a genome-wide CRISPR knockout screen to identify mediator genes.
- Performed transcriptomic analyses to explore affected cellular pathways.
Main Results:
- CGS-15943 demonstrated potent inhibition of lung cancer cell growth, contingent on AHR expression.
- AHR knockout significantly rescued cells from CGS-15943-induced death, confirming AHR's essential role.
- The heme biosynthesis pathway, heme-containing enzymes, AHR, and ARNT were identified as critical determinants of cell death.
- Transcriptomic data revealed AHR-dependent enrichment of oxidative stress and oxidized phospholipid response pathways.
Conclusions:
- CGS-15943 effectively triggers AHR-dependent programmed cell death in lung cancer.
- The identified AHR signaling network involves heme biosynthesis and oxidative stress responses.
- CGS-15943 represents a promising lead compound for targeting AHR-positive lung cancers.
