Abstract 443: PKC epsilon is activated by ionizing radiation in a reactive nitrogen species dependent manner in tumor endothelial cells.

PKCε is activated by ionizing radiation in a reactive nitrogen species dependent manner in tumor endothelial cells.

Ionizing radiation (IR) has been shown to increase angiogenic markers and migration in endothelial cells involving reactive oxygen/nitrogen species and eNOS, but the exact mechanism is poorly understood. This activation of endothelial cells can increase angiogenesis post radiation and confer cytoprotection to tumor cells. Thus targeting this IR induced activation of endothelial cells should increase therapeutic efficacy of radiation therapy. Protein Kinase C Epsilon is a molecule that has been shown to be important in cancer cell motility, proliferation, hormone sensitivity and angiogenesis. PKCε activates downstream pathways involved in tumorigenicity such as Akt and Stat3. PKCε has also been shown to be nitrated in response to NO donors and inflammatory conditions in cardiac myocytes. During inflammation, hypoxia and irradiation, levels of reactive nitrogen species are elevated due to uncoupling of Nitric Oxide Synthase (NOS). NOS can be recoupled with tetrahydrobiopterin precursor (sepiapterin) which decreases RNS/ROS in cells. We have shown in 2H11 cells (mouse tumor endothelial cells) that PKCε levels are increased due to exposure to clinically relevant doses of ionizing radiation or levels of NO found in chronic inflammatory conditions. Also in these cells PKCε is nitrated in response to reactive nitrogen species which leads to its activation and activation of Stat3 and Akt. Using sepiapterin, we have shown decreased levels of PKCε, Stat3 and Akt. We have also blocked ionizing radiation induced migration in vitro in 2H11 cells using sepiapterin and a PKCε inhibitor. We hope to show that PKCε is nitrated at specific residue(s) after ionizing radiation and activates tumor endothelial cells to promote the survival of the tumor. We believe sepiapterin with ionizing radiation therapy will result in increase cytotoxicity in a spontaneous mouse model of lung cancer, by decreasing endothelial activation, migration, proliferation and angiogenesis.

Citation Format: Asim Alam, Chris Rabender, Ross Mikkelsen. PKC epsilon is activated by ionizing radiation in a reactive nitrogen species dependent manner in tumor endothelial cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 443. doi:10.1158/1538-7445.AM2013-443

Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.