Introduction: Prostate cancer (PCa) progression is known to depend on various hormones and growth factors, but their role and underlying molecular mechanisms remain poorly understood. We recently presented preliminary findings indicating that leptin causes a greater level of activation of the JAK2/STAT3 and MAPK (ERK1/2) pathways, as well as transactivation of HER2, in androgen-sensitive LNCaP cells than in androgen-insensitive PC3 and DU145 human PCa cell lines. We and others were previously unable to demonstrate proliferative effects of leptin in LNCaP cells. We now studied the effects of leptin on LNCaP cell apoptotic proteins stimulated by starvation medium-induced stress via the intrinsic pathway, as well as on androgen receptor (AR) protein expression.
Results: Leptin (0.110 ng/ml; 672 h) caused clear apoptotic effects, seen as an increase in the downstream apoptotic effector caspase 3 protein expression (≤2.3-fold; av.±S.E.M.: 1.86±0.09) and in cleaved (inactivated) poly-(ADP-ribose)-polymerase (cPARP89), an enzyme normally responsible for DNA repair and a downstream substrate of caspase 3 (≤2.1-fold; av.±S.E.M.: 1.60±0.26). Leptin also caused increased expression of AR protein (≤2.6-fold; av.±S.E.M.: 1.96±0.34). All of these leptin effects were mostly maximal at 0.11.0 ng/ml and already at 6 h and generally still maintained at 10 ng/ml and for up to 72 h or gradually reduced (caspase 3) from 24 to 72 h. With view to understanding the mechanism of these leptin effects, we studied the effects of the JAK2 inhibitor AG490 on leptin-induced signalling and apoptotic and AR proteins. In a preliminary experiment, leptin-induced pJAK2 and pAKT (10 min) were clearly inhibited by AG490, while the inhibitor had lesser effects on leptin-induced apoptotic and AR proteins (6 h).
Conclusions: Clearly, further studies with other kinase inhibitors will be needed to delineate the mechanism of leptin-induced apoptosis in human PCa and its relationship with the effects of leptin on AR. These studies are expected to provide new insights into the possible role of leptin, presumably together with other hormones and growth factors, in the progression of human PCa or its delay, and may provide a basis for discovery of new drugs for therapy of PCa.
03 - 07 May 2008
European Society of Endocrinology