Budgeting at the Ca2+ store: a PIP(2)eline to starve LSCs?. (January 2021)

• Record Type: Journal Article
• Authors: Monaco, Giovanni; Percio, Stefano; Ting, Stephen B.
• Is Part Of: Cell calcium. Volume 93(2021)
• Publication Date: 2021-01
• Subjects: Calcium -- Metabolism -- Periodicals; Vertebrates -- Physiology -- Periodicals; Calcium -- Physiological effect -- Periodicals; Cell physiology -- Periodicals; Calcium in the body -- Periodicals; 572.516
• DOI: 10.1016/j.ceca.2020.102309
• Languages: English
• ISSNs: 0143-4160

Abstract

Graphical abstract: Highlights: ORP4L is proposed to extract PM-PIP2 and foster ER-Ca 2+ -dependent bioenergetics in LSCs. This ORPs/Ca 2+ link is bolstered by recent insights on ORP2/ORP1L roles for PIP2 trafficking. ORPphilines are anticipated to curb ER-mitochondria Ca 2+ fluxes and drain LSC bioenergetics. Critical analysis and therapeutic perspective in AML is provided. Abstract: The oxysterol-binding protein-related proteins (ORPs) have emerged as orchestrators of phosphatidylinositol-4, 5-bisphosphate (PIP2 ) and cholesterol trafficking to the plasma membrane (PM). In this scenario, recent studies raised the prospect of ORPs cooperative behavior in sustaining leukemia stem cells (LSCs) survival by remotely enhancing ER-mitochondria Ca 2+ communication. At the apex of the signaling cascade, the aberrantly upregulated LSC-ORP4L fosters PM-PIP2 extraction & cleavage, endoplasmic reticulum (ER)-Ca 2+ release and mitochondrial energetics. The theoretical ember of draining fuel from the chemoresistant LSCs by restraining endoplasmic reticulum (ER)-mitochondria Ca 2+ fluxes in a lipid-contingent fashion ensues. In light of relevant literature, this review briefly and critically discusses some key molecular ins & outs underlying such therapeutic opportunity in acute myeloid leukemia (AML).