WASHINGTON, DC USA (UroToday.com) - Apoptosis maintains homeostasis in developing and normally developed cells.
Cell surface receptors are critical to apoptosis. Death receptors activate caspases and other pathways to induce apoptosis. There is also an intrinsic pathway via mitochondira. The TNF and FAS receptor pathways are the best characterized. Although their experimental activation led to cell death, clinical utility was limited and secondary to toxicity. The TRAIL receptors however, induce apoptosis but do not induce toxicity in normal cells. The Decoy receptors such as OPG actually do not induce apoptosis. C-FLIP(L) regulates TRAIL signaling. They found numerous AP-1 and c-Fos binding sites regulating transcription. AP-1 sites regulate FOS-JUN transcriptional gene activation. C-Fos is overexpression in many different cancers, and they found has a pro-apoptotic function. C-Fos inhibits c-FLIP, and there were 14 potential promoter region-binding sites. C-Fos, however only bound to c-FLIP at one site in a CpG island. Mutation of this AP-1 site abrogates binding of c-Fos. Thus, c-Fos represses to c-FLIP’s ability to induce apoptosis. They found that FBXL10 could directly bind and repress the c-Fos promoter. The suppression of FBXL10 improved pro-apoptotic therapy in xenograft mouse models. The metabolic state of the cell determines sensitivity to pro-apoptotic therapies. Nutrient deficiency can cause metabolic stress. Metformin is an oral anti-hyperglycemic and targets complex I of the mitochondrial respiratory chain. Metformin shifts cellular metabolism and activates pro-apoptotic proteins, such as c-Fos. FBXL10 is downregulated with metformin.
Presented by Aria F. Olumi, MD at the Society for Basic Urologic Research (SBUR)/Society of Urologic Oncology (SUO) joint meeting during the American Urological Association (AUA) Annual Meeting - May 14 - 19, 2011 - Walter E. Washington Convention Center, Washington, DC USA
Reported for UroToday by Christopher P. Evans, MD, FACS, Professor and Chairman, Department of Urology, University of California, Davis, School of Medicine.
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