IGFBP3 and MAPK/ERK signaling mediates melatonin‐induced antitumor activity in prostate cancer

Abstract

Treatment of prostate cancer (PCa), a leading cause of cancer among males, lacks successful strategies especially in advanced, hormone-refractory stages. Some clinical studies have shown an increase in neuroendocrine-like cells parallel to the tumor progression but their exact role is a matter of debate. The prostate is a well-known target for melatonin, which reduces PCa cells proliferation and induces neuroendocrine differentiation. To evaluate the mechanisms underlying the indole effects on neuroendocrine differentiation and its impact on PCa progression, we used a cell culture model (LNCaP) and a murine model (TRAMP). Persistent ERK1/2 activation was found in both, melatonin and androgen-deprived cells. Melatonin blocked nuclear translocation of androgen receptor (AR), thus confirming anti-androgenic actions of the indole. However, using a comparative genome microarray to check the differentially expressed genes in control, melatonin, or androgen-deprived cells, some differences were found, suggesting a more complex role of the indole. By comparing control cells with those treated with melatonin or depleted of androgen, a cluster of 26 differentially expressed genes (±2.5-fold) was found. Kallikreins (KLK)2 and KLK3 (PSA) were dramatically downregulated by both treatments whereas IGFBP3 and IGF1R were up- and downregulated, respectively, in both experimental groups, thus showing a role for IGF in both scenarios. Finally, melatonin prolonged the survival of TRAMP mice by 33% when given at the beginning or at advances stages of the tumor. Serum IGFBP3 was significantly elevated by the indole in early stages of the tumor, confirming in vivo the role of the IGF signaling in the oncostatic action of the indole.

Melatonin, a Full Service Anti-Cancer Agent: Inhibition of Initiation, Progression and Metastasis

“…These findings suggest either anti-inflammatory or immunostimulatory functions of melatonin in augmenting the host defense against cancer progression. Interestingly, melatonin has been shown to promote the neuroendocrine (NE) differentiation of prostate cancer cells [293,294]. In general, NE cellular transdifferentiation supports the aggressive outgrowth of existing prostate tumors in an androgen-independent manner, and facilitates the development of resistance to anticancer therapy [295].…”

“…Melatonin induced the appearance of long dendritic-like extensions and smaller, rounded cell bodies, a morphological change similar to that occurring when prostate cancer cells undergo NE differentiation. However, distinct molecular features, including NE markers and gene expression patterns were not detected in response to melatonin compared with regular differentiation signals such as androgen withdrawal [294]. Melatonin administration prolonged the life span of TRAMP (transgenic adenocarcinoma of the mouse prostate) mice, which is a classical model of NE carcinoma [296], and effectively blocked tumor growth [294].…”

“…However, distinct molecular features, including NE markers and gene expression patterns were not detected in response to melatonin compared with regular differentiation signals such as androgen withdrawal [294]. Melatonin administration prolonged the life span of TRAMP (transgenic adenocarcinoma of the mouse prostate) mice, which is a classical model of NE carcinoma [296], and effectively blocked tumor growth [294]. Thus, how exactly melatonin triggers NE differentiation of prostate cancer cells, and whether this process contributes to tumor suppressive activity of the indoleamine is still a matter of debate.…”

“…P53 was also reported to participate in the pro-apoptotic action of melatonin in prostate cancer cells, as the indoleamine repressed the levels of negative regulators of p53 including MDM2 and Sirt1 [224,283]. NE differentiation triggered by chronic treatment with melatonin was independent of melatonin membrane receptors or the PKA activity [293], but required the persistent activation of ERK/MAPK pathway [294]. Moreover, melatonin attenuated the levels of HIF-1α protein by abrogation of p70S6K/RPS6/eIF4B pathway [305], which is responsible for the translation of HIF-1α gene [306].…”

Bone morphogenetic protein 2 promotes human trophoblast cell invasion and endothelial‐like tube formation through ID1‐mediated upregulation of IGF binding protein‐3

“…52 In prostate cancer, increased expression of ID1 promotes cancer cell invasion and is associated with poor prognosis of patients, [53][54][55][56] whereas IGFBP3 is thought to suppress cancer progression and is associated with better survival. 57,58 These opposing functions in prostate cancer may explain their inverse correlation in terms of expression. In human trophoblast cells, ID1 and IGFBP3 are both upregulated during villous cytotrophoblast differentiation to column EVTs.…”