Mechanisms of Ferroptotic Cancer Cell Death

Document text

Principal Investigator: Daolin  Tang
Organization: UT SOUTHWESTERN MEDICAL CENTER
Fiscal Year: 2024
Award: $353,971
Funding agency: National Cancer Institute

Abstract
 Ferroptosis is a recently recognized form of regulated cell death driven by lipid peroxidation. It is an emerging
field in cancer biology, and the detailed molecular regulators of ferroptosis are largely unknown. We recently
demonstrated that upregulation of metallothionein (MT)-1G expression contributes to ferroptosis resistance in
human hepatocellular carcinoma cells, whereas inhibition of MT-1G expression enhances ferroptosis sensitivity
in vitro and in vivo (Hepatology. 2016 63(1):173-184.; Hepatology. 2016 64(2):488-500.). These exciting findings
raise several important questions regarding the previously unidentified role of MT-1G in the regulation of
ferroptotic cancer cell death. Our central hypothesis is that expression and release of MT-1G limits ferroptotic
cancer cell death. To test this hypothesis, we will exploit molecular, cellular, and animal models to pursue the
following aims. Aim 1: Define the mechanism responsible for transcriptional regulation of MT-1G expression in
ferroptosis. Aim 2: Define the mechanism responsible for phosphorylation modification of MT-1G function in
ferroptosis. Aim 3: Define the mechanism responsible for extracellular activity of MT-1G in ferroptosis. The
completion of these exciting studies will improve our understanding of the cancer molecular pathobiology of
ferroptosis and guide future development of novel MT-1G-based anticancer therapeutic strategies.

Terms: <AGE receptor><AKT><Akt protein><Alanine><Amphoterin><Amphoterin Gene><Animal Model><Animal Models and Related Studies><Apoptosis><Apoptosis Pathway><BAY 54-9085><Basal Transcription Factor><Basal transcription factor genes><C-terminal><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cancer Biology><Cancer Cause><Cancer Etiology><Cancers><Carcinoma Cell><Caspase><Caspase Gene><Cell Body><Cell Death><Cell model><Cell-Death Protease><Cells><Cellular model><Cessation of life><Chromosomal Protein, Nonhistone, HMG1><Chromosomal Protein, Nonhistone, HMG1 Gene><Clinical><Complex><Cysteine Endopeptidases><Cysteine Protease><Cysteine Proteinases><Death><Development><Drugs><FES><FM1 Gene Product><FPS><FPS-FES Oncogene><Fujinami Sarcoma Virus and Feline Sarcoma Virus Transforming Gene><Future><GSK-3beta><GSK-3β><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Glycyrrhizic Acid><Glycyrrhizin><Glycyrrhizinic Acid><HIF 1 alpha><HIF-1alpha><HIF1-Alpha><HIF1A><HIF1A gene><HIF1α><HMG-1><HMG-1 Gene><HMG-1 Protein><HMG1><HMG1 Gene><HMG3><HMG3 Gene><HMGB1><HMGB1 Protein><HMGB1 gene><Heparin-Binding Protein p30><Hepatocarcinoma><Hepatocellular Carcinoma><Hepatocellular cancer><Hepatology><Hepatoma><High Mobility Group Box Protein 1><High Mobility Group Protein 1><High Mobility Group Protein 1 Gene><High-Mobility Group (Nonhistone Chromosomal) Protein 1><High-Mobility Group (Nonhistone Chromosomal) Protein 1 Gene><High-Mobility Group Box 1><High-Mobility Group Box 1 Gene><Homolog of Drosophila TOLL><Human><ICE-like protease><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><In Vitro><KO mice><Kinases><Knock-out Mice><Knockout Mice><L-Serine><Lipid Peroxidation><Liver Cells Carcinoma><MOP1><Malignant Cell><Malignant Epithelial Cell><Malignant Neoplasms><Malignant Tumor><Mediating><Medication><Metallothionein><Mice><Mice Mammals><Modern Man><Modification><Molecular><Molecular Modeling Nucleic Acid Biochemistry><Molecular Modeling Protein/Amino Acid Biochemistry><Molecular Models><Murine><Mus><Mutation><Nonhistone Chromosomal Protein HGM1><Nonhistone Chromosomal Protein HGM1 Gene><Nuclear><Null Mouse><Oncogene FES><Pathway interactions><Pharmaceutical Preparations><Phosphorylation><Phosphotransferase Gene><Phosphotransferases><Plasmids><Play><Primary carcinoma of the liver cells><Programmed Cell Death><Protein Kinase B><Protein Phosphorylation><Protein-Serine Kinase><Protein-Serine-Threonine Kinases><Protein-Threonine Kinase><Proteins><Proto-Oncogene Proteins c-akt><RAC-PK protein><RAGE receptor><RNA Expression><Receptor Activation><Regulation><Resistance><Role><SBP-1><SBP-1 Gene><Salazosulfapyridine><Salicylazosulfapyridine><Serine><Serine Kinase><Serine-Threonine Kinases><Serine/Threonine Protein Kinase Gene><Site><Sorafenib><Sulfasalazine><Sulfoglucuronyl Carbohydrate Binding Protein><Sulfoglucuronyl Carbohydrate Binding Protein Gene><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><TLR4><TLR4 gene><Testing><Threonine Kinase><Toll Homologue><Transcription><Transcription Factor Proto-Oncogene><Transcription Regulation><Transcription factor genes><Transcriptional Control><Transcriptional Regulation><Transphosphorylases><Tumor Cell><Tumor Immunity><Up-Regulation><Upregulation><advanced glycosylation end product receptor><amphoterin receptor><anti-cancer therapeutic><anti-tumor immune response><anti-tumor immunity><antitumor immunity><c-akt protein><cancer cell><cancer immunity><cofactor><conditional knock-out><conditional knockout><cystein protease><cystein proteinase><cysteine endopeptidase><developmental><drug/agent><erastin><exosome><extracellular><genome mutation><glycogen synthase kinase 3 beta><glycogen synthase kinase 3β><immune suppression><immune suppressive activity><immune suppressive function><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><in vivo><inhibitor><insight><liver carcinoma><malignancy><model of animal><molecular modeling><mutant><necrocytosis><neoplasm/cancer><neoplastic cell><neutralizing antibody><novel><pathway><proto-oncogene protein RAC><proto-oncogene protein akt><rac protein kinase><receptor for AGE><receptor for advanced glycation end product><receptor for advanced glycation endproducts><receptor of AGE><related to A and C-protein><resistant><shRNA><short hairpin RNA><small hairpin RNA><social role><thymus derived lymphocyte><toll-like receptor 4><transcription factor><tumor>