NEDD9 Inhibition by miR-25-5p Activation Is Critically Involved in Co-Treatment of Melatonin- and Pterostilbene-Induced Apoptosis in Colorectal Cancer Cells

Abstract

The underlying interaction between melatonin (MLT) and daily fruit intake still remains unclear to date, despite multibiological effects of MLT. Herein, the apoptotic mechanism by co-treatment of MLT and pterostilbene (Ptero) contained mainly in grape and blueberries was elucidated in colorectal cancers (CRCs). MLT and Ptero co-treatment (MLT+Ptero) showed synergistic cytotoxicity compared with MLT or Ptero alone, reduced the number of colonies and Ki67 expression, and also increased terminal deoxynucleotidyl transferase dUTP nick end labeling- (TUNEL) positive cells and reactive oxygen species (ROS) production in CRCs. Consistently, MLT+Ptero cleaved caspase 3 and poly (ADP-ribose) polymerase (PARP), activated sex-determining region Y-Box10 (SOX10), and also attenuated the expression of Bcl-xL, neural precursor cell expressed developmentally downregulated protein 9 (NEDD9), and SOX9 in CRCs. Additionally, MLT+Ptero induced differentially expressed microRNAs (upregulation: miR-25-5p, miR-542-5p, miR-711, miR-4725-3p, and miR-4484; downregulation: miR-4504, miR-668-3p, miR-3121-5p, miR-195-3p, and miR-5194) in HT29 cells. Consistently, MLT +Ptero upregulated miR-25-5p at mRNA level and conversely NEDD9 overexpression or miR-25-5p inhibitor reversed the ability of MLT+Ptero to increase cytotoxicity, suppress colony formation, and cleave PARP in CRCs. Furthermore, immunofluorescence confirmed miR-25-5p inhibitor reversed the reduced fluorescence of NEDD9 and increased SOX10 by MLT+Ptero in HT29 cells. Taken together, our findings provided evidence that MLT+Ptero enhances apoptosis via miR-25-5p mediated NEDD9 inhibition in colon cancer cells as a potent strategy for colorectal cancer therapy.

Colocalization of MID1IP1 and c-Myc is Critically Involved in Liver Cancer Growth via Regulation of Ribosomal Protein L5 and L11 and CNOT2

“…As shown in Jung et al's paper [28], HepG2 and Huh7 cells transfected with MID1IP1 siRNA or scramble siRNA control were cultured for 72 h, fixed in permeabilization solution and incubated with TUNEL assay mixture for 60 min. The TUNEL-stained cells were observed under a FLUOVIEW FV10i confocal microscope (Olympus, Tokyo, Japan).…”

A meta‐analysis of microRNA networks regulated by melatonin in cancer: Portrait of potential candidates for breast cancer treatment

“…We initially performed a systematic meta-analysis to identify miRNA expression profiles targeted by melatonin in experimentally relevant studies. Based on the design criteria for eligibility ( Figure 1), 14 studies [47][48][49][50][51][52][53][54][55][56][57][58][59][60] were selected to investigate the miRNAs expression changes induced by melatonin treatment (Table S1). Among the 46 differentially expressed miRNAs, 29 were upregulated, and 17 were downregulated (Table S2).…”

“…Since melatonin modulates different cellular responses observed in these cancer types, the genes shared among the tumors may reveal candidates for the treatment and management of the disease. Figure 3B depicts breast cancer sharing the highest number of genes that were upregulated (48) or downregulated by miRNAs (47); circus plot displays the intersection and contribution of a shared set of genes between two or more cancers ( Figure S2A,B). Notably, while no common genes upregulated by miRNAs appeared in melatonin-treated cancers, six common genes changed by downregulated miR-NAs coexisted among breast, oral, and prostate cancers, and glioblastoma [PTEN, FOXO3, ETS1, ICAM1, SELE, and SSX2IP; drug signature database (DSigDB)-related melatonin in this gene set; P < .05, combined score = 53].…”

The crystal structure of (E)-2-(4-((4-fluorobenzyl)oxy)styryl)-4,6-dimethoxybenzaldehyde, C24H21FO4

“…Among them, pterostilbene (trans-3,5-dimethoxy-4′-hydroxystilbene) is a natural dimethyl ether analogue to resveratrol, which is classified as a phytoalexin [3]. Up to now, pterostilbene is found to have diverse biological benefits in the prevention and treatment of many diseases, such as anticancer [5][6][7], anti-inflammation [8][9][10], anti-diabetes [11], the prevention of cardiovascular and congitive function degeneration [12]. Consequently, pterostilbene has good potential to be evaluated for therapeutic use.…”