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Mechanisms of Ferroptotic Cancer Cell Death

铁死亡癌细胞死亡机制

基本信息

批准号：
10685307
负责人：
Daolin Tang
金额：
$ 36.89万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-13 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10685307
关键词：
Alanine Animal Model Apoptosis BAY 54-9085 C-terminal CD8-Positive T-Lymphocytes Cancer Biology Cancer Etiology Caspase Cell Death Cell model Cells Cessation of life Clinical Complex Development FPS-FES Oncogene Future Genetic Transcription Glycyrrhizic Acid HIF1A gene HMGB1 gene Hepatology Human Immunosuppression In Vitro Knockout Mice Lipid Peroxidation Malignant Epithelial Cell Malignant Neoplasms Mediating Metallothionein Modification Molecular Mus Mutation Nuclear Pathway interactions Pharmaceutical Preparations Phosphorylation Phosphotransferases Plasmids Play Primary carcinoma of the liver cells Protein-Serine-Threonine Kinases Proteins Proto-Oncogene Proteins c-akt Receptor Activation Regulation Resistance Role Serine Site Sulfasalazine T-Lymphocyte TLR4 gene Testing Transcriptional Regulation Tumor Immunity Up-Regulation anti-cancer therapeutic anti-tumor immune response cancer cell cofactor conditional knockout erastin exosome extracellular glycogen synthase kinase 3 beta improved in vivo inhibitor insight molecular modeling mutant neoplastic cell neutralizing antibody novel receptor for advanced glycation endproducts small hairpin RNA transcription factor tumor

项目摘要

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.

摘要铁凋亡是最近认识到的由脂质过氧化驱动的调节性细胞死亡形式。是新兴在癌症生物学领域，以及铁凋亡的详细分子调节剂在很大程度上是未知的。我们最近表明金属硫蛋白（MT）-1G表达的上调有助于铁凋亡抗性，人肝细胞癌细胞，而MT-1G表达的抑制增强铁凋亡敏感性体外和体内（肝脏学。2016 63（1）：173-184.;肝病学。2016 64（2）：488-500）。这些令人兴奋的发现提出了几个重要的问题，关于MT-1G在调节铁凋亡性癌细胞死亡。我们的中心假设是MT-1G的表达和释放限制了铁毒性。癌细胞死亡为了验证这一假设，我们将利用分子、细胞和动物模型来研究这一问题。的目标。目的1：明确MT-1G在人肝癌细胞中的转录调控机制。铁性下垂目的2：明确MT-1G功能磷酸化修饰的机制，铁性下垂目的3：阐明MT-1G在铁凋亡中的作用机制。的这些令人兴奋的研究的完成将提高我们对癌症分子病理学的理解，并指导未来基于MT-1G的新型抗癌治疗策略的开发。