Minerva Foundation Institute for Medical Research, Helsinki, Finland; Department of Anatomy, Faculty of Medicine, University of Helsinki, Finland.
Biochem Pharmacol. 2022 Feb;196:114455. doi: 10.1016/j.bcp.2021.114455. Epub 2021 Feb 5.
Oxysterol-binding protein -related proteins (ORPs) form a large family of intracellular lipid binding/transfer proteins. A number of ORPs are implicated in inter-organelle lipid transfer over membrane contacts sites, their mode of action involving in several cases the transfer of two lipids in opposite directions, termed countercurrent lipid transfer. A unifying feature appears to be the capacity to bind phosphatidylinositol polyphosphates (PIPs). These lipids are in some cases transported by ORPs from one organelle to another to drive the transfer of another lipid against its concentration gradient, while they in other cases may act as allosteric regulators of ORPs, or an ORP may introduce a PIP to an enzyme for catalysis. Dysregulation of several ORP family members is implicated in cancers, ORP3, -4, -5 and -8 being thus far the most studied examples. The most likely mechanisms underlying their associations with malignant growth are (i) impacts on PIP-mediated signaling events resulting in altered Ca homeostasis, bioenergetics, cell survival, proliferation, and migration, (ii) protein-protein interactions affecting the activity of signaling factors, and (iii) modification of cellular lipid transport in a way that facilitates the proliferation of malignant cells. In this review I discuss the existing functional evidence for the involvement of ORPs in cancerous growth, discuss the findings in the light of the putative mechanisms outlined above and the possibility of employing ORPs as targets of anti-cancer therapy.
氧化固醇结合蛋白相关蛋白（ORP）形成了一大类细胞内脂质结合/转运蛋白家族。许多 ORP 被牵连到细胞器间脂质通过膜接触点的转移，它们的作用模式涉及在几种情况下两种脂质的反向转移，称为逆流脂质转移。一个统一的特征似乎是结合磷脂酰肌醇多磷酸盐（PIPs）的能力。这些脂质在某些情况下被 ORP 从一个细胞器运输到另一个细胞器，以推动另一种脂质逆其浓度梯度转移，而在其他情况下，它们可能作为 ORP 的别构调节剂，或者 ORP 可能将 PIP 引入酶以进行催化。几种 ORP 家族成员的失调与癌症有关，因此迄今为止，ORP3、-4、-5 和 -8 是研究最多的例子。它们与恶性生长相关的最可能机制是：（i）对 PIP 介导的信号事件的影响导致 Ca 稳态、生物能量学、细胞存活、增殖和迁移改变，（ii）影响信号因子活性的蛋白质-蛋白质相互作用，以及（iii）以促进恶性细胞增殖的方式修饰细胞脂质转运。在这篇综述中，我讨论了 ORP 参与癌症生长的现有功能证据，根据上述假设机制和将 ORP 作为抗癌治疗靶点的可能性讨论了这些发现。
