Abstract
Growth signals, which typically originate from the surrounding microenvironment, are important for cells. However, when stimulation by growth factors becomes excessive and exceeds their threshold limit, deleterious effects may ensue. In patients with cancer, maintenance of tumors depends, at least in part, on growth factor stimulation, which can also facilitate cancer progression into advanced stages. This is particularly important when the tumor grows beyond its tissue boundaries or when it invades and colonizes other tissues. These aforementioned malignant events are known to be partly supported by elevated cytokine levels. Among the currently known growth signals, insulin-like growth factor (IGF)-1 and IL-6 have been previously studied for their roles in prostate cancer. Both IGF-1 and IL-6 have been reported to activate the RAPTOR independent companion of MTOR complex 2 (Rictor)/AKT/protein kinase C α (PKCα) signaling pathway as one of their downstream mechanisms. At present, research efforts are mainly focused on the exploration of agents that alter growth factor (such as IGF-1) and cytokine (such as IL-6) signaling for their potential application as therapeutic agents, as both of these have been reported to modulate disease outcome. In the present study, IGF-1 and IL-6 served distinct roles in the androgen responsive LNCaP cell line and in the androgen refractory PC-3 cell line in a dose- and time-dependent manner. Increased phosphorylation of Rictor at the Thr-1135 residue, AKT at the Ser-473 residue and PKCα at the Ser-657 residue were observed after treatment with IGF-1 and IL-6. Subsequently, it was found that diosmetin, a natural plant aglycone, had the potential to modulate the downstream signaling cascade of Rictor/AKT/PKCα to inhibit the progression of prostate cancer. Treatment of LNCaP and PC-3 cells with diosmetin inhibited the phosphorylation of Rictor (Thr-1135), AKT (Ser-473) and PKCα (Ser-657) in a dose-dependent manner. Furthermore, the Bax/Bcl-2 expression ratio was increased in response to diosmetin treatment, which would result in increased apoptosis. Based on these observations, diosmetin may represent a novel therapeutic target for prostate cancer.