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

doi:10.1016/j.isci.2023.107408

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

iScience. 2023 Jul 17;26(8):107408. doi: 10.1016/j.isci.2023.107408. eCollection 2023 Aug 18.

Authors

Debasmita Mukherjee^{1

2}, Srija Chakraborty^{1

3}, Lena Bercz¹, Liliana D'Alesio¹, Jessica Wedig^{1

2}, Molly A Torok¹, Timothy Pfau¹, Hannah Lathrop¹, Shrina Jasani¹, Abigail Guenther¹, Jake McGue⁴, Daniel Adu-Ampratwum⁵, James R Fuchs⁵, Timothy L Frankel⁴, Maciej Pietrzak⁶, Stacey Culp⁶, Anne M Strohecker^{1

7}, Aleksander Skardal^{1

3}, Thomas A Mace^{1

8}

Affiliations

¹ The James Comprehensive Cancer Center, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
² Molecular, Cellular and Developmental Biology Program, The Ohio State University, Columbus, OH 43210, USA.
³ Department of Biomedical Engineering, The Ohio State University, Columbus, OH 43210, USA.
⁴ Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
⁵ Division of Medicinal Chemistry & Pharmacognosy, The Ohio State University, Columbus, OH 43210, USA.
⁶ Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA.
⁷ Department of Cancer Biology & Genetics, The Ohio State University, Columbus, OH 43210, USA.
⁸ Department of Internal Medicine, Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University, Columbus, OH 43210, USA.

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.

Keywords: Cancer; Microenvironment; Therapeutics.