Mechanisms of Ferroptotic Cancer Cell Death

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。

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.