Targeting PPP1R15 in malignancy

癌症治疗的目标是在对正常组织没有伤害或最小伤害的情况下杀死恶性肿瘤细胞。这可以通过识别和定位癌细胞特有的特征来实现。癌症生物学中一个反复出现的主题是通常会导致癌细胞死亡的过程的失活。因此，反应这些过程的策略是开发新治疗方法的有希望的目标。因为癌细胞通常制造高水平的蛋白质，所以它们容易积聚错误合成的(所谓的“错误折叠”)蛋白质。错误折叠的蛋白质在细胞中被称为内质网(ER)的一部分积累，导致一种被称为内质网应激的毒性状态。这会减少细胞中蛋白质的合成，并在触发名为PERK的内质网应激传感器后激活保护过程。PERK似乎在癌症进展中很重要，因为缺乏PERK的癌细胞会形成较小的肿瘤，而阻断PERK的药物在研究研究中显示出作为抗癌剂的巨大前景。一种名为PPP1R15A的蛋白质通常反对PERK的作用，我们之前已经证明，PPP1R15A与内质网应激引起的一些细胞死亡有关。因此，失去PPP1R15A的细胞会受到PERK的更多保护，我们最近报道，一种称为恶性间皮瘤的高侵袭性癌症往往会失去PPP1R15A，这可能会增加癌症对内质网应激的抵抗力。在这个项目中，我们将探索靶向PPP1R15A在癌症治疗中的可能性。我们最近报道了PPP1R15A受一种名为G-肌动蛋白的蛋白质的丰富调控，G-肌动蛋白的水平对细胞生长信号和COIL运动敏感。我们将确定PPP1R15A和G-肌动蛋白之间的相互作用在健康中是如何调控的，以及对这种相互作用的操纵是否可以增加细胞中的PPP1R15A活性，因为这可能会增加抗癌PERK抑制剂的有效性。PPP1R15A是一种不稳定的蛋白质，可以在细胞内有效降解。我们将确定导致PPP1R15A降解的细胞机制，因为抑制这一机制可以恢复PPP1R15A的水平，从而增加内质网应激诱导的癌细胞杀伤。值得注意的是，PPP1R15A导致细胞毒性的确切机制尚不清楚。PPP1R15A可以与细胞成分结合，包括内质网、脂滴和线粒体，所有这些都对细胞生存至关重要。通过确定PPP1R15A结合对这些细胞结构功能的影响，我们将更好地了解这种蛋白的毒性作用。这些研究将使我们能够理解PPP1R15A从癌细胞中丢失的机制和功能后果。这在针对内质网应激的抗癌疗法的开发中将是重要的。

The goal of cancer therapy is to kill malignant cells with no or minimal harm to normal tissue. This can be achieved by identifying and targeting features specific to the cancer cell. A recurring theme in cancer biology is the inactivation of processes that would normally cause cancer cell death. Strategies that reactive these processes are therefore promising targets for the development of new treatments. Because cancer cells commonly make high levels of protein they are prone to accumulating incorrectly synthesised (so called 'misfolded') protein. The accumulation of misfolded protein in an a part of the cell called the endoplasmic reticulum (ER) leads to a toxic state called 'ER stress'. This reduces protein synthesis in the cell and activation of protective processes following the triggering of an ER stress sensor called PERK. PERK appears to be important in cancer progression because cancer cells lacking PERK form smaller tumours, while drugs that block PERK are showing great promise in research studies as anti-cancer agents. A protein called PPP1R15A normally opposes the action of PERK and we previously showed that PPP1R15A is responsible for some of the cell death caused by ER stress. Consequently, cells that have lost PPP1R15A experience more protective by PERK and we recently reported that highly aggressive forms of a cancer called malignant mesothelioma tend to lose PPP1R15A, possibly increasing the cancers resistance to ER stress.In this project we will explore the potential for targeting PPP1R15A in the treatment of cancer. We have recently reported that PPP1R15A is regulated by the abundance of a protein called G-actin, the levels of which are sensitive to cellular growth signals and to coll movement. We will determine how the interaction between PPP1R15A and G-actin in regulated in health and whether manipulation of this interaction can increase PPP1R15A activity in the cell, since this could potentially increase the effectiveness of anti-cancer PERK inhibitors. PPP1R15A is an unstable protein that is efficiently degraded within the cells. We will identify the cellular machinery that causes PPP1R15A degradation, since inhibition of this machinery could restore PPP1R15A levels and so increase ER stress-induced cancer cell killing. Remarkably, the precise mechanism by which PPP1R15A leads to cell toxicity remains unclear. PPP1R15A can bind to cellular components including the ER, lipid droplets and mitochondria, all of which are crucial for cellular survival. By determining the effect of PPP1R15A binding on the function of these cellular structures we will better understand the toxic effects of this protein.Together, these studies will enable us to understand the mechanism and functional consequences of PPP1R15A loss from cancer cells. This will be important in the development of anticancer therapies that target ER stress.