Tomatidine targets ATF4-dependent signaling and induces ferroptosis to limit pancreatic cancer progression.

Autor:	Mukherjee D; 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., Chakraborty S; 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., Bercz L; The James Comprehensive Cancer Center, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA., D'Alesio L; The James Comprehensive Cancer Center, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA., Wedig J; 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., Torok MA; The James Comprehensive Cancer Center, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA., Pfau T; The James Comprehensive Cancer Center, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA., Lathrop H; The James Comprehensive Cancer Center, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA., Jasani S; The James Comprehensive Cancer Center, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA., Guenther A; The James Comprehensive Cancer Center, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA., McGue J; Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA., Adu-Ampratwum D; Division of Medicinal Chemistry & Pharmacognosy, The Ohio State University, Columbus, OH 43210, USA., Fuchs JR; Division of Medicinal Chemistry & Pharmacognosy, The Ohio State University, Columbus, OH 43210, USA., Frankel TL; Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA., Pietrzak M; Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA., Culp S; Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA., Strohecker AM; 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., Skardal A; 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., Mace TA; 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.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2023 Jul 17; Vol. 26 (8), pp. 107408. Date of Electronic Publication: 2023 Jul 17 (Print Publication: 2023).
DOI:	10.1016/j.isci.2023.107408
Abstrakt:	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. Competing Interests: Authors declare that they have no potential conflicts of interest. (© 2023 The Author(s).)
Databáze:	MEDLINE
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