ORP4L is essential for T-cell acute lymphoblastic leukemia cell survival.

Abstract

Metabolic pathways are reprogrammed in cancer to support cell survival. Here, we report that T-cell acute lymphoblastic leukemia (T-ALL) cells are characterized by increased oxidative phosphorylation and robust ATP production. We demonstrate that ORP4L is expressed in T-ALL but not normal T-cells and its abundance is proportional to cellular ATP. ORP4L acts as an adaptor/scaffold assembling CD3ɛ, Gαq/11 and PLCβ3 into a complex that activates PLCβ3. PLCβ3 catalyzes IP3 production in T-ALL as opposed to PLCγ1 in normal T-cells. Up-regulation of ORP4L thus results in a switch in the enzyme responsible for IP3-induced endoplasmic reticulum Ca(2+) release and oxidative phosphorylation. ORP4L knockdown results in suboptimal bioenergetics, cell death and abrogation of T-ALL engraftment in vivo. In summary, we uncovered a signalling pathway operating specifically in T-ALL cells in which ORP4L mediates G protein-coupled ligand-induced PLCβ3 activation, resulting in an increase of mitochondrial respiration for cell survival. Targeting ORP4L might represent a promising approach for T-ALL treatment.

• Authors: Wenbin Zhong, Qing Yi, Bing Xu, Shiqian Li, Tong Wang, Fupei Liu, Biying Zhu, Peter R Hoffmann, Guangju Ji, Pingsheng Lei, Guoping Li, Jiwei Li, Jian Li, Vesa M Olkkonen, Daoguang Yan
• Journal: Nature communications (Nat Commun) Vol. 7 Pg. 12702 (09 01 2016) ISSN: 2041-1723 [Electronic] England
• PMID: 27581363 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Steroid
• oxysterol binding protein
• Adenosine Triphosphate
• PLCB3 protein, human
• Phospholipase C beta
• Calcium

Topics

• Adenosine Triphosphate (biosynthesis)
• Animals
• Calcium (metabolism)
• Calcium Signaling (physiology)
• Cell Line, Tumor
• Cell Survival (physiology)
• Endoplasmic Reticulum (metabolism)
• Female
• Humans
• Jurkat Cells
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Mitochondria (metabolism)
• Oxidative Phosphorylation
• Phospholipase C beta (metabolism)
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (pathology)
• Receptors, Steroid (biosynthesis)
• T-Lymphocytes (metabolism)