Melatonin Inhibits Androgen Receptor Splice Variant-7 (AR-V7)-Induced Nuclear Factor-Kappa B (NF-κB) Activation and NF-κB Activator-Induced AR-V7 Expression in Prostate Cancer Cells: Potential Implications for the Use of Melatonin in Castration-Resistant Prostate Cancer (CRPC) Therapy

Abstract

A major current challenge in the treatment of advanced prostate cancer, which can be initially controlled by medical or surgical castration, is the development of effective, safe, and affordable therapies against progression of the disease to the stage of castration resistance. Here, we showed that in LNCaP and 22Rv1 prostate cancer cells transiently overexpressing androgen receptor splice variant-7 (AR-V7), nuclear factor-kappa B (NF-κB) was activated and could result in up-regulated interleukin (IL)-6 gene expression, indicating a positive interaction between AR-V7 expression and activated NF-κB/IL-6 signaling in castration-resistant prostate cancer (CRPC) pathogenesis. Importantly, both AR-V7-induced NF-κB activation and IL-6 gene transcription in LNCaP and 22Rv1 cells could be inhibited by melatonin. Furthermore, stimulation of AR-V7 mRNA expression in LNCaP cells by betulinic acid, a pharmacological NF-κB activator, was reduced by melatonin treatment. Our data support the presence of bi-directional positive interactions between AR-V7 expression and NF-κB activation in CRPC pathogenesis. Of note, melatonin, by inhibiting NF-κB activation via the previously-reported MT1 receptor-mediated antiproliferative pathway, can disrupt these bi-directional positive interactions between AR-V7 and NF-κB and thereby delay the development of castration resistance in advanced prostate cancer. Apparently, this therapeutic potential of melatonin in advanced prostate cancer/CRPC management is worth translation in the clinic via combined androgen depletion and melatonin repletion.

Mitochondria: the birth place, battle ground and the site of melatonin metabolism in cells

“…In the normal cells, the reversed equilibrium is expected since melatonin protects normal cell from apoptosis and other cellular injuries (65)(66)(67)(68)(69). Many studies have observed that melatonin treatment has beneficial effects on normal cells but induces apoptosis in tumor cells (70)(71)(72)(73)(74). Under melatonin treatment, large quantity of cytochrome C is released from the mitochondria into cytosol to induce apoptosis in tumor cells (75)(76)(77) while and the cytochrome C release is inhibited in the normal cells by melatonin (75,(78)(79)(80).…”

Melatonin and Hippo Pathway: Is There Existing Cross-Talk?

“…Conversely, in other systems such as Cos7 fibroblasts, HEK293 and MCF7 cells, activation of Gαq and Gαs proteins coupled to MT1 receptors leads to an increase of cAMP formation. Increased intracellular cAMP in turn activates PKA and PKC, which causes the inhibition of NF-ΚB (Nuclear Factor Kappa-light-chain-enhancer of activated B cells) with consequent derepression of the oncosuppressor p27 kip1 and attenuation of the androgen response in prostate cells [ 53 , 54 , 55 , 65 , 66 , 67 ], activation of JNK in Cos7 cells [ 68 ], and phosphorylation of ERK1/2 in HEK 293 cells [ 69 ].…”

“…Moreover, melatonin has been shown to inhibit the expression of stemness-related genes, [ 105 , 128 , 129 ] to inhibit stemness-related pathways [ 105 , 106 ] to improve the response to several anticancer therapies [ 102 , 103 , 130 , 131 , 132 , 133 , 134 ], and to inhibit angiogenesis [ 127 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 ]. Finally, in Androgen Receptor (AR) and Estrogen Receptor (ER) positive cells, melatonin inhibits the AR [ 54 , 65 , 147 , 148 , 149 ] and ER response [ 128 , 150 , 151 , 152 , 153 ] through different mechanisms either mediated by MT1 or independent of MT1 receptor binding.…”

“…Similarly, melatonin has been shown to activate Gαs proteins associated with MT1 receptors in prostate cell lines [ 53 , 54 , 55 , 65 , 66 , 67 ], Cos-7 cells [ 68 ], and HEK293 cells [ 69 ], as well as to increase intracellular cAMP with subsequent activation of PKA and PKC. Thus, the activation of PKA and PKC mediated by Gαs in response to different stimuli (glucagon, epinephrine, dobutamine, melatonin) may lead to inhibition of cell proliferation and invasiveness through multiple converging mechanisms, including LATS1/2 activation [ 203 , 204 , 205 ] and, as mentioned above, inhibition of NF-κB transcriptional activity and inhibition of the AR response in AR positive cells [ 55 ].…”

Inhibition of SIRT1 by microRNA-9, the key point in process of LPS-induced severe inflammation

“…NF-κB pathway regulates the expression of a large number of genes, which are crucial for the regulation of apoptosis, virus replication, tumorigenesis, inflammation and various autoimmune diseases [11][12][13][14]. Bacterial infection or LPS simulation activates NF-κB pathway which promotes the production of inflammatory cytokines [15].…”