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

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...

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Published in:iScience 2023-08, Vol.26 (8), p.107408, Article 107408
Main Authors: Mukherjee, Debasmita, Chakraborty, Srija, Bercz, Lena, D’Alesio, Liliana, Wedig, Jessica, Torok, Molly A., Pfau, Timothy, Lathrop, Hannah, Jasani, Shrina, Guenther, Abigail, McGue, Jake, Adu-Ampratwum, Daniel, Fuchs, James R., Frankel, Timothy L., Pietrzak, Maciej, Culp, Stacey, Strohecker, Anne M., Skardal, Aleksander, Mace, Thomas A.
Format: Article
Language:English
Subjects:
Cancer
Microenvironment
Therapeutics
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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. [Display omitted] •ATF4, a transcription factor regulating stress, is a target in pancreatic cancer•Tomatidine inhibits pancreatic tumor growth and enhances gemcitabine chemosensitivity•Tomatidine reduces binding of ATF4 with downstream promoter elements•Tomatidine induces ferroptosis-mediated cell death in pancreatic cancer cells Therapeutics; Microenvironment; Cancer
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2023.107408