Abstract 3631: NMDA receptors as possible therapeutic targets for cancer

Abstract

Abstract NMDA receptors constitute important calcium channels that are chiefly found within the central nervous system. Our laboratory has shown that these receptors are also expressed by human tumors such as neuroblastoma, small-cell lung carcinoma, breast cancer, and now ovarian and prostate cancer. The hypothesis being tested in our studies is that selective tumor expression of NMDA receptors is essential for cancer cell growth and proliferation. Human breast and ovarian cancer cells were treated with NMDA antagonists and agonists and changes measured in cell proliferation/growth and apoptosis. It was shown NMDA receptors are critically involved in cell growth of these cancer cells, and if blocked, cell growth is inhibited. Interestingly, the non-cancerous cell line, HEK 293, also expresses NMDA receptors, but NMDA antagonists were found to not influence growth of these cells. Receptor knock-down in MCF-7 breast cancer cells is being accomplished with lentavirus-coupled shRNAs, and selection performed for puromyocin resistance. We have thus far been able to selectively stably reduce NMDA receptor expression by 70-80% for a period of two weeks. The rate of cell growth was significantly decreased when the expression level of NMDAR1 is knocked down. The response of NMDA receptor knock-down cells to antagonists such as MK-801 and Mementine will be examined. Confirmation that the actions of antagonists such as MK-801 on cancer growth are specifically due to blockade of NMDA receptors will further their potential future use in cancer treatment. By confocal microscopy we were able to demonstrate that breast, ovarian, and prostate cancer cells express NMDA receptors within the membrane of tumor cells. Treating breast cancer cells with NMDA receptor antagonists and an antibody against an extracellular region of the subunit 1 changes the sub-cellular localization of these NMDA receptors. This change in sub-cellular localization could be an indicator of the mechanism of action of these compounds on cancer cell growth through the expression levels of the receptors. Additional studies are now being performed using sub-cellular fractionation and fluorescent microscopy to determine the nature of NMDAR1 cellular translocalization. The goal of this project is to further evaluate NMDA receptors as possible targets for treatment of breast cancer and perhaps several other cancer types. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3631. doi:10.1158/1538-7445.AM2011-3631