Tomatidine targets ATF4-dependent signaling and induces ferroptosis to limit pancreatic cancer progression
Debasmita Mukherjee,
Srija Chakraborty,
Lena Bercz,
Liliana D’Alesio,
Jessica Wedig,
Molly A. Torok,
Timothy Pfau,
Hannah Lathrop,
Shrina Jasani,
Abigail Guenther,
Jake McGue,
Daniel Adu-Ampratwum,
James R. Fuchs,
Timothy L. Frankel,
Maciej Pietrzak,
Stacey Culp,
Anne M. Strohecker,
Aleksander Skardal,
Thomas A. Mace
Affiliations
Debasmita Mukherjee
The James Comprehensive Cancer Center, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Molecular, Cellular and Developmental Biology Program, The Ohio State University, Columbus, OH 43210, USA
Srija Chakraborty
The James Comprehensive Cancer Center, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Department of Biomedical Engineering, The Ohio State University, Columbus, OH 43210, USA
Lena Bercz
The James Comprehensive Cancer Center, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Liliana D’Alesio
The James Comprehensive Cancer Center, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Jessica Wedig
The James Comprehensive Cancer Center, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Molecular, Cellular and Developmental Biology Program, The Ohio State University, Columbus, OH 43210, USA
Molly A. Torok
The James Comprehensive Cancer Center, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Timothy Pfau
The James Comprehensive Cancer Center, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Hannah Lathrop
The James Comprehensive Cancer Center, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Shrina Jasani
The James Comprehensive Cancer Center, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Abigail Guenther
The James Comprehensive Cancer Center, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Jake McGue
Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
Daniel Adu-Ampratwum
Division of Medicinal Chemistry & Pharmacognosy, The Ohio State University, Columbus, OH 43210, USA
James R. Fuchs
Division of Medicinal Chemistry & Pharmacognosy, The Ohio State University, Columbus, OH 43210, USA
Timothy L. Frankel
Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA
Maciej Pietrzak
Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA
Stacey Culp
Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA
Anne M. Strohecker
The James Comprehensive Cancer Center, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Department of Cancer Biology & Genetics, The Ohio State University, Columbus, OH 43210, USA
Aleksander Skardal
The James Comprehensive Cancer Center, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Department of Biomedical Engineering, The Ohio State University, Columbus, OH 43210, USA
Thomas A. Mace
The James Comprehensive Cancer Center, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA; Department of Internal Medicine, Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University, Columbus, OH 43210, USA; Corresponding author
Summary: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with high metastasis and therapeutic resistance. Activating transcription factor 4 (ATF4), a master regulator of cellular stress, is exploited by cancer cells to survive. Prior research and data reported provide evidence that high ATF4 expression correlates with worse overall survival in PDAC. Tomatidine, a natural steroidal alkaloid, is associated with inhibition of ATF4 signaling in multiple diseases. Here, we discovered that in vitro and in vivo tomatidine treatment of PDAC cells inhibits tumor growth. Tomatidine inhibited nuclear translocation of ATF4 and reduced the transcriptional binding of ATF4 with downstream promoters. Tomatidine enhanced gemcitabine chemosensitivity in 3D ECM-hydrogels and in vivo. Tomatidine treatment was associated with induction of ferroptosis signaling validated by increased lipid peroxidation, mitochondrial biogenesis, and decreased GPX4 expression in PDAC cells. This study highlights a possible therapeutic approach utilizing a plant-derived metabolite, tomatidine, to target ATF4 activity in PDAC.
