Gonadotropin-Releasing Hormone Induces Apoptosis of Prostate Cancer Cells

Abstract

A standard therapy used today for prostate cancer is androgen ablation by gonadotropin-releasing hormone analogs (GnRH-a). Although most patients respond to androgen ablation as an initial systemic therapy, nearly all cases will develop androgen resistance, the management of which is still a major challenge. Here, we report that GnRH-a can directly induce apoptosis of the androgen-independent prostate cancer-derived DU145 and PC3 cell lines. Using specific inhibitors, we found that the apoptotic effect of GnRH-a is mediated by c-Jun NH 2 -terminal kinase (JNK) and inhibited by the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB) pathway. Indeed, in DU145 cells, GnRH-a activates the JNK cascade in a c-Src-and MLK3-dependent manner but does not involve protein kinase C and epidermal growth factor receptor. Concomitantly, GnRH-a reduces the activity of the PI3K-PKB pathway, which results in the dephosphorylation of PKB mainly in the nucleus. The reduction of PKB activity releases PKB-induced inhibition of MLK3 and thus further stimulates JNK activity and accelerates the apoptotic effect of GnRH-a. Interestingly, extracellular signal-regulated kinase is also activated by GnRH-a, and this occurs via a pathway that involves matrix metalloproteinases and epidermal growth factor receptor, but its activation does not affect JNK activation and the GnRH-a-induced apoptosis. Our results support a potential use of GnRH-a for the treatment of advanced prostate cancer and suggest that the outcome of this treatment can be amplified by using PI3K-PKB inhibitors.

Gq Protein-induced Apoptosis Is Mediated by AKT Kinase Inhibition That Leads to Protein Kinase C-induced c-Jun N-terminal Kinase Activation

“…We then analyzed two systems in which G q PCRs were implicated in growth arrest and apoptosis. In both cell lines, stimulation of the examined G q PCR induced apoptosis by activating the same signaling pathway that seems similar to the one identified in prostate cancer cells (16). Thus, our results indicate that upon stimulation, G q transmit its apoptotic signal first by inducing activation of PKC that transmits it further by two separate signaling branches.…”

“…Four of them were cells in which AKT phosphorylation was reduced and JNK phosphorylation was elevated. These results, together with our previous finding with DU145 cells (16), suggest a common linkage of PKC, AKT, and JNK to apoptosis in many cells. Thus, unlike previous thoughts, the PKC-induced AKT inactivation that leads to JNK phosphorylation and apoptosis seems to be a widespread signaling process that is worth further study.…”

“…In a previous study we found that GnRH not only inhibits growth factor-stimulated AKT activation, but can also reduce the high basal phosphorylation of this kinase in prostate cancer cells (16). This reduced phosphorylation and activity alleviate the inhibitory effects of AKT on the proapoptotic JNK cascade and therefore induced cell death.…”

“…Lines-In a previous study we found that GnRH reduces the high basal phosphorylation of AKT in starved prostate cancer cells, and this led to JNK activation and apoptosis (16). Because it is usually assumed that stimuli should activate AKT rather than inactivating it, we undertook first to study how general this phenomenon is.…”

“…Aside from these G q PCRinduced effects, these central receptors were also implicated in growth arrest or apoptosis in few pathological systems (11)(12)(13). For instance, cardiac hypertrophy seems to be mediated by auto/paracrine mediators acting through G q PCRs (14,15), and gonadotropin-releasing hormone (GnRH) was shown to induce apoptosis of prostate cancer cells through its G q PCR (16). Surprisingly, overexpression of constitutively active form of G q was found to induce apoptosis of COS7, CHO (17), and HeLa (18) cells as well.…”