Talk abstracts
Talk on Tuesday 03:15-03:30pm submitted by Debi Mukherjee
Tomatidine therapeutically targets ATF4 to limit pancreatic cancer progression
Debasmita Mukherjee (Molecular, Cellular, and Developmental Biology Program Graduate Program), Lena Bercz, Liliana DAlesio, Jessica Wedig, Hannah Lathrop (The James Comprehensive Cancer Center, The Ohio State University), Srija Chakroborty, Aleksander Skardal (Department of Biomedical Engineering, The Ohio State University), Thomas A. Mace (Department of Internal Medicine, Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University)
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) is a lethal and aggressive cancer with a five-year survival rate of only 13%. Current therapies are often ineffective due to late detection and high metastasis rates. Therefore, there is a necessity to build novel therapies to combat PDAC. Our work provides evidence that high expression of Activating Transcription Factor 4 (ATF4) in the PDAC tumor microenvironment corresponds to worse overall survival in PDAC patients. Cancer cells exploit ATF4 to adapt to cellular stress and avoid cell death. Tomatidine, a natural steroidal alkaloid, has been associated with inhibition of ATF4-dependent signaling in multiple diseases. We hypothesized that tomatidine targets ATF4-dependent signaling and can be developed as an anti-cancer therapeutic in pancreatic cancer. We discovered in vitro and in vivo tomatidine treatment of PDAC cells significantly inhibits tumor growth. Immunofluorescence staining of ATF4 in tomatidine treated PDAC cells suggested tomatidine restricted nuclear translocation of ATF4. Chromatin immunoprecipitation revealed that tomatidine reduced the binding of ATF4 with promoter region of its downstream genes, suggesting tomatidine inhibits ATF4 activity. Further, tomatidine significantly enhanced sensitivity of other chemotherapies used for pancreatic cancer patients in 3D ECM-hydrogels as well as in an orthotopic model of pancreatic cancer in vivo. Finally, tomatidine treatment was associated with induction of ferroptosis signaling in PDAC cells. Hallmarks of ferroptosis was validated by observing increased lipid peroxidation through C11 Bodipy assay using flow cytometry, decreased GPX4 expression via immunoblotting, and enhanced mitochondrial respiratory capacity measured via seahorse assay in tomatidine treated PDAC cells. Overall, my research highlights a novel plant-derived therapeutic, tomatidine, that targets ATF4 activity and induces ferroptosis to limit PDAC progression.
Keywords: Pancreatic cancer, ATF4, Ferroptosis