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 CD3?, G?q/11 and PLC?3 into a complex that activates PLC?3. PLC?3 catalyzes IP3 production in T-ALL as opposed to PLC?1 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 PLC?3 activation, resulting in an increase of mitochondrial respiration for cell survival. Targeting ORP4L might represent a promising approach for T-ALL treatment.

SUBMITTER: Zhong W 

PROVIDER: S-EPMC5025801 | biostudies-other | 2016 Sep

REPOSITORIES: biostudies-other