Melatonin induces apoptotic death in LNCaP cells via p38 and JNK pathways: therapeutic implications for prostate cancer

Abstract

Apoptosis, a form of cell death, is a fundamental process for the development and maintenance of multicellular organisms that promotes the removal of damaged, senescent or unwanted cells. Induction of cancer cell apoptosis is an important strategy of anticancer therapy. In this study, we examined if melatonin, the main secretory product of the pineal gland, inhibited the growth of prostate cancer cells (LNCaP) and promoted apoptosis via mitogen-activated protein kinases (MAPKs), which are closely associated with apoptosis and survival. Melatonin treatment significantly inhibited the growth of LNCaP cells in a dose- and time-dependent manner. It clearly induced both an early stage of apoptosis (propidium iodide(-), FITC Annexin-V(+)) and a late apoptosis/secondary necrosis (propidium iodide(+) and FITC Annexin-V(+)), which indicated induction of serial stages of apoptosis in cells. Moreover, melatonin markedly activated c-JUN N-terminal kinase (JNK) and p38 kinase, whereas extracellular signal-regulated kinase (ERK) was not responsive to melatonin. Treatment with MAPK inhibitors, PD98059 (ERK inhibitor), SP600125 (JNK inhibitor) and SB202190 (p38 inhibitor), confirmed that melatonin-induced apoptosis was JNK- and p38-dependent, but ERK-independent. In the presence of PD98059, caspase-3 activity increased, while levels of Bax/cytochrome c (Cyt c) and Bcl-2 decreased. These effects were opposite to those observed with SP600125 and SB202190 treatments. Together, these results strongly suggest that JNK and p38 activation directly participate in apoptosis induced by melatonin. Thus, melatonin may be of promise for anti-prostate cancer strategies.

Melatonin Induces Apoptotic Cell Death via p53 in LNCaP Cells

“…We confirmed that melatonin caused apoptosis by p53 phosphorylation at serine 15, increasing the expression of downstream signals such as MDM2 and p21 in LNCaP cells; this is similar to our previous data, which indicated that melatonin induced caspase-3 activation and cytochrome c and Bax release into the cytosol [13]. However, MAPK inhibitors, SP600125 and SB202190, caused the down-regulation of p-p53, p21, and MDM2 after a co-treatment with melatonin, while PD98059 did not affect the expressions of p-p53, p21, or MDM2 during cell death induced by melatonin, indicating that the JNK and p38 MAPK pathways are closely associated with p53 phosphorylation.…”

“…In our previous research, we found that melatonin markedly activated JNK and p38 kinase. Treatment with PD98059 (ERK inhibitor), SP600125 (JNK inhibitor) and SB202190 (p38 inhibitor) confirmed that melatonin-induced apoptosis was JNK-and p38-dependent, but ERK-independent [13]. Here, we showed that melatonin increases the expressions of p53 and p21.…”

“…Our previous study demonstrated that melatonin results in apoptosis and induces oncostasis via modulation of signaling mediated by JNK and p38 MAPK in LNCaP prostate cancer cells and that melatonin may play an important role in androgen-dependent prostate cancer as an apoptotic and oncostatic anti-cancer agent [13]. The present report shows that melatonin also induces apoptotic cell death in LNCaP prostate cancer cells via signaling mediated by p53.…”

“…For example, the signal pathway via the JNK and p38 MAPK in LNCaP cells is activated by melatonin [13]. In our previous research, we found that melatonin markedly activated JNK and p38 kinase.…”

“…Many recent reports have shown that melatonin inhibits the growth of androgen-sensitive human LNCaP prostate cancer cells [9][10][11][12]. In our previous report, we demonstrated that melatonin is able to induce apoptotic cell death in LNCaP cells via the p38 and c-JUN N-terminal kinase (JNK) pathways [13]. Here, we determined whether melatonin induced apoptosis via signaling mediated by p53 in LNCaP cells.…”