Auranofin reveals therapeutic anticancer potential by triggering distinct molecular cell death mechanisms and innate immunity in mutant p53 non-small cell lung cancer
Laurie Freire Boullosa,
Jinthe Van Loenhout,
Tal Flieswasser,
Jorrit De Waele,
Christophe Hermans,
Hilde Lambrechts,
Bart Cuypers,
Kris Laukens,
Esther Bartholomeus,
Vasiliki Siozopoulou,
Winnok H. De Vos,
Marc Peeters,
Evelien L.J. Smits,
Christophe Deben
Affiliations
Laurie Freire Boullosa
Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Wilrijk, Belgium; Corresponding authorCenter for Oncological Research (CORE), University of Antwerp, Universiteitsplein 1, 2610, Wilrijk (Antwerp), Belgium.
Jinthe Van Loenhout
Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Wilrijk, Belgium
Tal Flieswasser
Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Wilrijk, Belgium
Jorrit De Waele
Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Wilrijk, Belgium
Christophe Hermans
Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Wilrijk, Belgium; Department of Pathology, Antwerp University Hospital, Edegem, Belgium
Hilde Lambrechts
Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Wilrijk, Belgium
Bart Cuypers
Adrem Data Lab, Department of Computer Science, University of Antwerp, Antwerp, Belgium; Molecular Parasitology Unit, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium
Kris Laukens
Adrem Data Lab, Department of Computer Science, University of Antwerp, Antwerp, Belgium
Esther Bartholomeus
Department of Medical Genetics, University of Antwerp, Antwerp University Hospital, Edegem, Belgium
Vasiliki Siozopoulou
Department of Pathology, Antwerp University Hospital, Edegem, Belgium
Winnok H. De Vos
Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Wilrijk, Belgium
Marc Peeters
Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Wilrijk, Belgium; Department of Oncology, Multidisciplinary Oncological Center Antwerp, Antwerp University Hospital, Edegem, Belgium
Evelien L.J. Smits
Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Wilrijk, Belgium; Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Edegem, Belgium
Christophe Deben
Center for Oncological Research (CORE), Integrated Personalized & Precision Oncology Network (IPPON), University of Antwerp, Wilrijk, Belgium
Auranofin (AF) is an FDA-approved antirheumatic drug with anticancer properties that acts as a thioredoxin reductase 1 (TrxR) inhibitor. The exact mechanisms through which AF targets cancer cells remain elusive. To shed light on the mode of action, this study provides an in-depth analysis on the molecular mechanisms and immunogenicity of AF-mediated cytotoxicity in the non-small cell lung cancer (NSCLC) cell line NCI–H1299 (p53 Null) and its two isogenic derivates with mutant p53 R175H or R273H accumulation.TrxR is highly expressed in a panel of 72 NSCLC patients, making it a valid druggable target in NSCLC for AF. The presence of mutant p53 overexpression was identified as an important sensitizer for AF in (isogenic) NSCLC cells as it was correlated with reduced thioredoxin (Trx) levels in vitro. Transcriptome analysis revealed dysregulation of genes involved in oxidative stress response, DNA damage, granzyme A (GZMA) signaling and ferroptosis. Although functionally AF appeared a potent inhibitor of GPX4 in all NCI–H1299 cell lines, the induction of lipid peroxidation and consequently ferroptosis was limited to the p53 R273H expressing cells. In the p53 R175H cells, AF mainly induced large-scale DNA damage and replication stress, leading to the induction of apoptotic cell death rather than ferroptosis. Importantly, all cell death types were immunogenic since the release of danger signals (ecto-calreticulin, ATP and HMGB1) and dendritic cell maturation occurred irrespective of (mutant) p53 expression. Finally, we show that AF sensitized cancer cells to caspase-independent natural killer cell-mediated killing by downregulation of several key targets of GZMA.Our data provides novel insights on AF as a potent, clinically available, off-patent cancer drug by targeting mutant p53 cancer cells through distinct cell death mechanisms (apoptosis and ferroptosis). In addition, AF improves the innate immune response at both cytostatic (natural killer cell-mediated killing) and cytotoxic concentrations (dendritic cell maturation).
