Frigo, Daniel E.2019-09-132019-09-13May 20172017-05May 2017https://hdl.handle.net/10657/4533Prostate cancer is a hormone-driven malignancy that relies on the function of the androgen receptor (AR). AR is a transcription factor that regulates the expression of many downstream targets, some of which can facilitate an important hallmark of cancer; metabolic reprogramming. Metabolic reprogramming allows the cancer to maintain an aberrant metabolism that supports uncontrolled cellular growth and survival. This reprogramming if often initiated by signaling pathways essential for growth and survival. There are therapies available that target AR signaling but they inevitably fail. Therefore, I sought to identify new potential targets that are downstream of AR and other oncogenic signals in prostate cancer and define the mechanism through which they are regulated. First, I investigated how two glutamine transporters, SLC1A4 and SLC1A5 (Solute Carrier Family 1A, members 4 and 5) were regulated in glutamine-addicted prostate cancer cells. I found that the transporters were hormone-responsive but not direct targets of AR. Downstream of AR they are regulated via mammalian target of rapamycin (mTOR) signaling and selectively regulated via MYC. Importantly I determined that SLC1A4 and SLC1A5 represented a central node of several oncogenic signaling pathways that controlled overall cell growth, making them promising targets for prostate cancer therapy. Next, I investigated the regulation of glucose uptake through SLC2A12 (GLUT12 (glucose transporter 12)). I found that SLC2A12 is a direct target of AR and is required for prostate cancer cell growth. GLUT12 is also regulated through calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2)-5’-AMP-activated protein kinase (AMPK) signaling. CaMKK2-AMPK activity promotes GLUT12 translocation to the plasma membrane via modulation of TBC1D4 (TBC1 Domain Family Member 4) and also regulation of TBC1D4 expression. Taken together my findings demonstrate that SLC1A4, SLC1A5, and SLC2A12 all have the potential to be prostate cancer therapeutic targets due to their modulation by major oncogenic signaling pathways and their functional role in cancer cell growth. Their essential role in cancer cell growth and easily accessible location on the cell surface suggest these proteins may be readily druggable. Thus, my findings highlight the utility of targeting pathogenic metabolism as a therapy and provide potential starting points for future translational research.application/pdfengThe author of this work is the copyright owner. UH Libraries and the Texas Digital Library have their permission to store and provide access to this work. Further transmission, reproduction, or presentation of this work is prohibited except with permission of the author(s).GlutamineGlucose metabolismProstate cancerMYCMTORSLC1A4SLC1A5AMPKCaMKK2SLC2A12GLUT12TBC1D42019-09-13Thesisborn digital