Abstract 35: Diacylglycerol kinase zeta-mediated regulation of mTOR and SREBP-1 offers new opportunities for cancer management

Diacylglycerol (DAG) and phosphatidic acid (PA) are two lipids that lie at the core of several metabolic and signaling pathways, which allows integrated control of cell growth and nutrient sensing with cell metabolism. Diacylglycerol kinases (DGK) are a family of enzymes that balance the levels of both lipids. Some DGK isoforms, mainly DGKα, have been recently suggested as potential targets for cancer treatment (Dominguez et al, 2013; Torres-Ayuso et al, 2014). Previous observations from us indicate that the DGKζ isoform contributes the most to DGK activity in cancer cells, and DGKζ-derived PA is required for mTOR activation, a master regulator of cell growth and metabolism (Avila-Flores et al, 2005).To address the potential of DGKζ as new therapeutic target for cancer treatment, we used several breast and colon cancer cell lines, and analyzed the effect of its pharmacological inhibition or siRNA-mediated knock down in the proliferation, survival and metabolism of these cells.We found that DGKζ protein levels where higher in malignant cells compared to their non-transformed counterparts, and its depletion abrogated cancer cell growth in colony assays. DGKζ was prominent over other PA sources to activate mTOR, and its activity was induced by rapamycin. We also investigated whether DGKζ-derived PA functions were coordinated with DAG metabolism and signaling. We observed that DGKζ-dependent DAG consumption was crucial for cell homeostasis via control of the SREBP-1 trans...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Molecular and Cellular Biology Source Type: research