Mechanisms of Ferroptotic Cancer Cell Death

摘要 铁下垂是最近公认的一种由脂质过氧化引起的调节性细胞死亡。它是一种新兴的 在癌症生物学领域，铁下垂的详细分子调节机制在很大程度上是未知的。我们最近 金属硫蛋白(MT)-1G表达上调与铁下垂抵抗有关 抑制MT-1G表达增强铁下垂敏感性 体外和体内(肝脏学。2016年63(1)：173-184；肝脏科。2016年(2)：488-500。)这些令人兴奋的发现 就MT-1G在调节中的作用提出几个重要问题 铁眼性癌细胞死亡。我们的中心假设是MT-1G的表达和释放限制了铁下垂 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 遵循目标。目的1：明确MT-1G基因转录调控机制 铁性下垂。目的2：明确MT-1G功能的磷酸化修饰机制 铁性下垂。目的3：明确MT-1G在铁性下垂中的胞外活性机制。这个 这些令人兴奋的研究的完成将提高我们对癌症分子病理生物学的理解。 并指导基于MT-1G的新型抗癌治疗策略的未来发展。

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.