Organic Selenium induces ferroptosis in pancreatic cancer cells
Roberta Noè,
Noemi Inglese,
Patrizia Romani,
Thauan Serafini,
Carlotta Paoli,
Beatrice Calciolari,
Marco Fantuz,
Agata Zamborlin,
Nicoletta C. Surdo,
Vittoria Spada,
Martina Spacci,
Sara Volta,
Maria Laura Ermini,
Giulietta Di Benedetto,
Valentina Frusca,
Claudio Santi,
Konstantinos Lefkimmiatis,
Sirio Dupont,
Valerio Voliani,
Luca Sancineto,
Alessandro Carrer
Affiliations
Roberta Noè
Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy; Department of Biology, University of Padova, 35126, Padova, Italy
Noemi Inglese
Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy; Department of Biology, University of Padova, 35126, Padova, Italy
Patrizia Romani
Department of Molecular Medicine, University of Padova, 35126, Padova, Italy
Thauan Serafini
Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy
Carlotta Paoli
Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy; Department of Biology, University of Padova, 35126, Padova, Italy
Beatrice Calciolari
Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy; Department of Biology, University of Padova, 35126, Padova, Italy
Marco Fantuz
Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy; Department of Biology, University of Padova, 35126, Padova, Italy
Agata Zamborlin
NEST-Scuola Normale Superiore, 56127, Pisa, Italy; Center for Nanotechnology Innovation, Istituto Italiano di Tecnologia, 56127, Pisa, Italy
Nicoletta C. Surdo
Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy; Neuroscience Institute, National Research Council (CNR), 35121, Padova, Italy
Vittoria Spada
Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy
Martina Spacci
Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy; Department of Biology, University of Padova, 35126, Padova, Italy
Sara Volta
Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy
Maria Laura Ermini
Center for Nanotechnology Innovation, Istituto Italiano di Tecnologia, 56127, Pisa, Italy
Giulietta Di Benedetto
Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy; Neuroscience Institute, National Research Council (CNR), 35121, Padova, Italy
Valentina Frusca
Center for Nanotechnology Innovation, Istituto Italiano di Tecnologia, 56127, Pisa, Italy; Scuola Superiore Sant’Anna, Piazza Martiri della Libertà 33, 56127, Pisa, Italy
Claudio Santi
Group of Catalysis and Green Organic Chemistry, Department of Pharmaceutical Sciences, University of Perugia, 06122, Perugia, PG, Italy
Konstantinos Lefkimmiatis
Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy; Department of Molecular Medicine, University of Pavia, Pavia, Italy
Sirio Dupont
Department of Molecular Medicine, University of Padova, 35126, Padova, Italy
Valerio Voliani
Center for Nanotechnology Innovation, Istituto Italiano di Tecnologia, 56127, Pisa, Italy; Department of Pharmacy, School of Medical and Pharmaceutical Sciences, University of Genova, 16148, Genoa, Italy; Corresponding author. Department of Pharmacy, School of Medical and Pharmaceutical Sciences, University of Genoa, 16148, Genoa, Italy.
Luca Sancineto
Group of Catalysis and Green Organic Chemistry, Department of Pharmaceutical Sciences, University of Perugia, 06122, Perugia, PG, Italy; Corresponding author. Department of Pharmaceutical Sciences, University of Perugia.
Alessandro Carrer
Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy; Department of Biology, University of Padova, 35126, Padova, Italy; Corresponding author. Veneto Institute of Molecular Medicine (VIMM), 35129, Padova, Italy.
Pancreatic ductal adenocarcinoma (PDA) cells reprogram both mitochondrial and lysosomal functions to support growth. At the same time, this causes significant dishomeostasis of free radicals. While this is compensated by the upregulation of detoxification mechanisms, it also represents a potential vulnerability.Here we demonstrate that PDA cells are sensitive to the inhibition of the mevalonate pathway (MVP), which supports the biosynthesis of critical antioxidant intermediates and protect from ferroptosis. We attacked the susceptibility of PDA cells to ferroptotic death with selenorganic compounds, including dibenzyl diselenide (DBDS) that exhibits potent pro-oxidant properties and inhibits tumor growth in vitro and in vivo. DBDS treatment induces the mobilization of iron from mitochondria enabling uncontrolled lipid peroxidation. Finally, we showed that DBDS and statins act synergistically to promote ferroptosis and provide evidence that combined treatment is a viable strategy to combat PDA.
