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
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.
iScience. 2023 Jul 17;26(8):107408. doi: 10.1016/j.isci.2023.107408. eCollection 2023 Aug 18.
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.
胰腺导管腺癌（PDAC）是一种具有高转移性和治疗抗性的侵袭性癌症。激活转录因子4（ATF4）是细胞应激的主要调节因子，癌细胞利用它来存活。先前的研究和报告数据表明，ATF4高表达与PDAC患者较差的总生存期相关。番茄碱是一种天然甾体生物碱，在多种疾病中与抑制ATF4信号传导有关。在这里，我们发现番茄碱处理PDAC细胞可抑制肿瘤生长。番茄碱抑制ATF4的核转位，并减少ATF4与下游启动子的转录结合。番茄碱增强了吉西他滨在3D细胞外基质水凝胶中的化疗敏感性。番茄碱处理与铁死亡信号的诱导有关，PDAC细胞中脂质过氧化增加、线粒体生物合成增加以及GPX4表达降低验证了这一点。这项研究突出了一种利用植物衍生代谢物番茄碱靶向PDAC中ATF4活性的可能治疗方法。
