The emerging roles of OSBP-related proteins in cancer: Impacts through phosphoinositide metabolism and protein-protein interactions

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 Ca2+ 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.