How do tumor cells lose their dependence on circulating hormones?
When prostate tumors are advanced, men are often treated with androgen deprivation therapy. Tumors initially respond by regressing but inevitably recur, no longer dependent on circulating testosterone. Normal prostate cells have a finely tuned system for responding to androgens that involves irreversible inactivation by glucuronidation when they are in excess. The enzymes that control glucuronidation are also androgen controlled. We are examining how altered expression of glucuronidation enzymes may impact flux of androgens through the cell’s synthetic pathways, and how the tumor cell’s response to hormones is affected. We are also investigating ways to use combinations of small molecule pharmaceuticals and/or dietary interventions to optimize the hormone elimination pathways and sensitize tumors to chemotherapy.
Potential role of UGDH in prostate tumor cell androgen response. Testosterone, synthesized at the tissue level or delivered in circulation, enters the luminal/tumor cell and is converted to DHT. Both testosterone and DHT are substrates of UGT2B15/17, which use the UGDH product UDP-glucuronate (UDP-GlcA) as a cofactor for glucuronidation and inactivation of these steroids. UGDH is DHT-stimulated in the ligand-dependent AR pathway and drives glucuronidation, which is thought to be a negative feedback regulator to rid the cell of excess androgen. Since the affinity of UGTs for androgen is lower than that of the AR, significant elevation of UDP-GlcA is needed to drop cellular androgens below the level of cellular response. This elevation, found in luminal cells of cancerous acini, could promote ligand-independent function of the AR.