Back to Search Start Over

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

Authors :
Mukherjee D
Chakraborty S
Bercz L
D'Alesio L
Wedig J
Torok MA
Pfau T
Lathrop H
Jasani S
Guenther A
McGue J
Adu-Ampratwum D
Fuchs JR
Frankel TL
Pietrzak M
Culp S
Strohecker AM
Skardal A
Mace TA
Source :
IScience [iScience] 2023 Jul 17; Vol. 26 (8), pp. 107408. Date of Electronic Publication: 2023 Jul 17 (Print Publication: 2023).
Publication Year :
2023

Abstract

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.<br />Competing Interests: Authors declare that they have no potential conflicts of interest.<br /> (© 2023 The Author(s).)

Details

Language :
English
ISSN :
2589-0042
Volume :
26
Issue :
8
Database :
MEDLINE
Journal :
IScience
Publication Type :
Academic Journal
Accession number :
37554459
Full Text :
https://doi.org/10.1016/j.isci.2023.107408