The Defender against apoptotic cell death (DAD1) is a negative regulator of programmed cell death that was initially identified in the temperature sensitive tsBN7 cell line. It has been shown to be an essential subunit of oligosaccharyltransferase and is localized to the Endoplasmic reticulum (ER) in a normal physiological state. However, our data suggests that DAD1 localizes outside of the cell and alters the apoptotic signaling via FAS ligand to give cancer cells a survival advantage. Although the mechanism is poorly understood, increased expression of DAD1 has been associated with increasing Gleason score in prostate cancer (PCa) patient tumors. Based on the aforementioned evidence, our study attempts to unravel cellular localization and the underlying mechanisms by which DAD1 mediates prostate cancer cell survival, and explore its potential as a biomarker in prostate cancer. As evidenced by qRTPCR, immunocytochemistry, immunohistochemistry, Co-ip, ELISA, and immuno-blot analysis, cancer cells down regulate the expression of the binding partner of DAD1 responsible for retention of DAD1 in the ER, which allows DAD1 to exit the ER and be exocytosed. The exocytosed DAD1 binds to FAS L and prevents apoptotic signaling. Treatment with DAD1 antibody induces significantly higher cell death in prostate cancer cells compared to the non-tumorigenic cells. Combination of DAD1 antibody with currently used chemotherapeutic agents like Docetaxel and Doxorubicin can be used to achieve higher cell death at a lower dose of these drugs to minimize side effects. Further, our immunohistochemistry data in tumor microarray suggests that DAD1 could serve as a potential biomarker marker in PCa. In addition to the tissue, we also examined the expression of DAD1 in prostate cancer patient serum samples using sandwich ELISA; our results indicate DAD1 is a more sensitive and specific prognostic marker for prostate cancer compared to PSA. Our data suggests that localization of DAD1 outside of the cells is crucial to the survival of PCa cells and this phenomenon can be exploited to specifically target prostate cancer cells in therapy and serve as a biomarker in prostate cancer. / 1 / Nobel Bhasin
| Identifer | oai:union.ndltd.org:TULANE/oai:http://digitallibrary.tulane.edu/:tulane_45957 |
| Date | January 2015 |
| Contributors | Bhasin, Nobel D. (author), Mageed, Asim Abdel (Thesis advisor), School of Medicine Biomedical Sciences Graduate Program (Degree granting institution) |
| Source Sets | Tulane University |
| Language | English |
| Detected Language | English |
| Type | Text |
| Format | electronic |
| Rights | No embargo |
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