Tomatidine Targets ATF4-dependent Signaling and Induces Ferroptosis to Limit Pancreatic Cancer Progression

Overview

Journal iScience

Publisher Cell Press

Date 2023 Aug 9

PMID 37554459

Authors

Debasmita Mukherjee

Srija Chakraborty

Lena Bercz

Liliana DAlesio

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

Soon will be listed here.

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 and 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 . 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.

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