Benign prostatic hyperplasia (BPH) in humans originates primarily from the abnormal proliferation of the peri-urethral smooth muscle cells (PUSMC) between the verumontanum and bladder neck. When clinically manifest, the tissue mass of the adenoma is 80% fibromuscular stroma. Spontaneous neoplasia of smooth muscle cells does not occur in either the true prostate gland or seminal vesicle. Development of pharmacotherapeutic modalities to control BPH must therefore be directed at regulating the proliferation/differentiation state of this PUSMC. We hypothesize that the modulation of protein kinase C (PKC) activity and effects is a major regulatory system in PUSMC and as such represents a key target for drug therapy. It is the goal of this research program to test the hypotheses that: 1) PKC activation, including the functional interaction of the enzyme with its specific receptor sites, is intimately linked to androgen sensitive human peri-urethral smooth muscle proliferation, 2) the progression of proliferating cells to the normal differentiated non-proliferative state requires PKC inactivation through inhibitory transmembrane signaling mechanisms and 3) that proliferating smooth muscle can be differentiated to the normal non-proliferative state with glucocorticoids and/or alpha-tocopherol by inactivating PKC or preventing its effects. New therapeutic concepts for BPH are envisioned based on the pharmacological induction of the differentiated non-proliferative state of peri-urethral smooth muscle cells of young adult males.
| Kim, Julie; Cole, Dennis; Johnson, Anne et al. (2002) Androgen induced norepinephrine release from postganglionic neurons mediates accessory sex organ smooth muscle proliferation. J Urol 167:1897-904 |
| Gebrosky, N; Cole, D; Stetter-Neel, C et al. (1997) m-Calpain activation/depletion is associated with androgen-induced reduction of protein kinase C and proliferation of male accessory sex organ smooth muscle cells. J Urol 157:662-8 |
