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 transcription factor, which was negatively regulated by DAG. Our data provide new evidence of the crosstalk between mTOR and lipid metabolism, and suggest that DGKζ represents an effective target for cancer control.

References

Avila-Flores A, Santos T, Rincon E, Merida I (2005) Modulation of the mammalian target of rapamycin pathway by diacylglycerol kinase-produced phosphatidic acid. The Journal of biological chemistry 280: 10091-10099

Dominguez CL, Floyd DH, Xiao A, Mullins GR, Kefas BA, Xin W, Yacur MN, Abounader R, Lee JK, Wilson GM, Harris TE, Purow BW (2013) Diacylglycerol kinase alpha is a critical signaling node and novel therapeutic target in glioblastoma and other cancers. Cancer discovery 3: 782-797

Torres-Ayuso P, Daza-Martin M, Martin-Perez J, Avila-Flores A, Merida I (2014) Diacylglycerol kinase alpha promotes 3D cancer cell growth and limits drug sensitivity through functional interaction with Src. Oncotarget 5: 9710-9726

Citation Format: PEDRO Torres-Ayuso, David Jones, Maria Tello-Lafoz, Antonia Avila-Flores, Isabel Merida. Diacylglycerol kinase zeta-mediated regulation of mTOR and SREBP-1 offers new opportunities for cancer management. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 35. doi:10.1158/1538-7445.AM2015-35

©2015 American Association for Cancer Research.
2015