Abstract 3561: UCP2’s tumor-promoting role via regulating lipid signaling and PLCγ -1 activity

Abstract

Abstract Mitochondrial abnormalities are long suspected to play important roles in tumor cell differentiation, proliferation and metabolism. Dysfunction of mitochondrial-dependent processes appear to be key features of cancerous cells. Among many such abnormal features of cancerous cells, a mitochondrial uncoupling protein 2 (UCP2) is shown to be up-regulated in various aggressive human cancers. Uncoupling proteins are a family of mitochondrial proteins present in the inner mitochondrial membrane whose physiological role is to decrease membrane potential and reactive oxygen species (ROS) production. UCP2 over-expression recently been proposed as a novel survival mechanism for cancer cells. However, till date, the exact role of UCP2 in cancer remains inconclusive. We recently reported that UCP2 appears to be a key regulator of cell proliferation, cell cycle and cell death during skin tumorigenesis. Using JB6P+ cells that overexpress UCP2, we showed that UCP2 expression correlated closely with cell proliferation and cell transformation. Moreover, inhibition of UCP2, decreased colony formation and 3D culture growth. Since UCP2 is the crucial player in the regulation of reactive oxygen species, and mitochondrial bioenergetics, we wanted to dissect out the role of UCP2 in redox regulation and tumor promotion. Our data demonstrated that UCP2 differentially regulated ROS. UCP2 upregulation, decreased superoxide production, whereas increased hydrogen peroxide production with a concomitant increase in manganese superoxide dismutase (MnSOD) expression and activity. Furthermore, hydrogen peroxide was responsible for induction of lipid peroxidation and PLCγ-1 activation in UCP2 overexpressed cells. Moreover, PLCγ-1 activation enhanced tumorigenecity. Strikingly, pharmacological and siRNA mediated inhibition of PLCγ-1 markedly reduced colony formation and 3D growth in vitro. Lastly, restricting hydrogen peroxide production with hydrogen peroxide scavenger catalase, suppressed lipid peroxidation and dampened PLCγ-1 activity. Taken together, our data suggest that hydrogen peroxide might be the mediator of UCP2’s tumor promoting role, and pharmacological disruption of PLCγ-1, and/or hydrogen peroxide may have clinical utility for UCP2-overexpressed cancers. This research was funded by NCI and Feist-Wellier Cancer Center of LSUHSC-S Citation Format: Annapoorna Sreedhar, Yunfeng Zhao. UCP2’s tumor-promoting role via regulating lipid signaling and PLCγ -1 activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3561. doi:10.1158/1538-7445.AM2017-3561