Anti-Proliferative Effect of Naringenin through p38-Dependent Downregulation of Cyclin D1 in Human Colorectal Cancer Cells

Song, Hun Min; Park, Gwang Hun; Lee, Jin Wook; Kim, Mi Kyoung; Lee, Jeong Rak; Lee, Man Hyo; Koo, Jin Suk; Jeong, Jin Boo

doi:10.4062/biomolther.2015.024

Cited by 50 publications

(19 citation statements)

References 37 publications

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“…The synthesis of AgNPs was carried out using a pure aqueous solution of NAR (50 µM) mixed with 2 mM silver nitrate at 37 °C for 1 h. NAR is a flavonoid with significant antibiotic, anti-cancerous, and anti-inflammatory properties against various types of cancer cells [26,27,28]. Color formation rapidly occurred in this mixture, possibly because of the reaction between Ag ions and NAR [12,28].…”

Section: Resultsmentioning

confidence: 99%

Cytotoxic Potential and Molecular Pathway Analysis of Silver Nanoparticles in Human Colon Cancer Cells HCT116

Gurunathan

Qasim

Park

et al. 2018

IJMS

137

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Silver nanoparticles (AgNPs) have gained attention for use in cancer therapy. In this study, AgNPs were biosynthesized using naringenin. We investigated the anti-colon cancer activities of biogenic AgNPs through transcriptome analysis using RNA sequencing, and the mechanisms of AgNPs in regulating colon cancer cell growth. The synthesized AgNPs were characterized using UV–visible spectroscopy (UV–vis), X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), dynamic light scattering (DLS), and transmission electron microscopy (TEM). The AgNPs were spherical with sizes of 2–10 nm. Cytotoxicity assays indicated that the AgNPs in HCT116 colorectal cancer cells were very effective at low concentrations. The viability and proliferation of colon cancer cells treated with 5 µg/mL biogenic AgNPs were reduced by 50%. Increased lactate dehydrogenase leakage (LDH), reactive oxygen species (ROS) generation, malondialdehyde (MDA), and decreased dead-cell protease activity and ATP generation were observed. This impaired mitochondrial function and DNA damage led to cell death. The AgNPs upregulated and downregulated the most highly ranked biological processes of oxidation–reduction and cell-cycle regulation, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that AgNPs upregulated GADD45G in the p53 pathway. Thus, the AgNP tumor suppressive effects were mediated by cell apoptosis following DNA damage, as well as by mitochondrial dysfunction and cell-cycle arrest following aberrant regulation of p53 effector proteins. It is of interest to mention that, to the best of our knowledge, this study is the first report demonstrating cellular responses and molecular pathways analysis of AgNPs in HCT116 colorectal cancer cells.

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Section: Resultsmentioning

confidence: 99%

Cytotoxic Potential and Molecular Pathway Analysis of Silver Nanoparticles in Human Colon Cancer Cells HCT116

Gurunathan

Qasim

Park

et al. 2018

IJMS

137

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“…There are observations indicating that ATF3 inhibits cancer cell proliferation through activating p53 ( Yan et al ., 2005 ; Wang et al ., 2010 ) and downregulating cyclin D1 by transcriptional suppression ( Lu et al ., 2006b ). We have reported that NAR downregulates cyclin D1 protein level but not mRNA level resulting in the growth arrest of human colon cancer cells ( Song et al ., 2015 ), which indicates that NAR-mediated downregulation of cyclin D1 may be independent on ATF3 activation. Although ATF3 has been regarded as a common molecular target for the proapoptotic effect, specific mechanisms for the apoptotic effect of ATF3 remain nuclear.…”

Section: Discussionmentioning

confidence: 99%

Naringenin-Mediated ATF3 Expression Contributes to Apoptosis in Human Colon Cancer

Song

Park

Jeong

2016

Biomolecules & Therapeutics

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Naringenin (NAR) as one of the flavonoids observed in grapefruit has been reported to exhibit an anti-cancer activity. Activating transcription factor 3 (ATF3) is associated with apoptosis in human colon cancer cells. This study was performed to investigate the molecular mechanism by which NAR stimulates ATF3 expression and apoptosis in human colon cancer cells. NAR reduced the cell viability and induced an apoptosis in human colon cancer cells. ATF3 overexpression increased NAR-mediated cleaved PARP, while ATF3 knockdown attenuated the cleavage of PARP by NAR. NAR increased ATF3 expression in both protein and mRNA level, and increased the luciferase activity of ATF3 promoter in a dose-dependent manner. The responsible region for ATF3 transcriptional activation by NAR is located between −317 and −148 of ATF3 promoter. p38 inhibition blocked NAR-mediated ATF3 expression, its promoter activation and apoptosis. The results suggest that NAR induces apoptosis through p38-dependent ATF3 activation in human colon cancer cells.

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“…The antigenantibody complexes were detected using ECL reagents with an ImageQuant LAS-4000 mini (GE Healthcare Life Sciences, Piscataway, NJ, USA). GAPDH or β-actin was used as the loading control (12).…”

Section: Methodsmentioning

confidence: 99%

Butyrate-mediated acquisition of chemoresistance by human colon cancer cells

et al. 2016

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Abstract. Butyrate is a short-chain fatty acid produced by the intestinal microflora and it not only induces apoptosis but also inhibits the proliferation of cancer cells. Recently, it has been reported that butyrate may cause resistance in colon cancer cells. Therefore, we investigated the effects of increased resistance to butyrate in HCT116 colon cancer cells. We established HCT116 cells resistant to butyrate (HCT116/ BR) by treating HCT116 parental cells (HCT116/PT) with increasing concentrations of butyrate to a maximum of 1.6 mM for 3 months. The butyrate concentrations that inhibited cell growth by 50% (IC 50 ) were 0.508 and 5.50 mM in HCT116/PT and HCT116/BR cells. The values after treatment with paclitaxel, 5-fluorouracil (5-FU), doxorubicin and trichostatin A (TSA) were 2.42, 2.36, 4.31 and 11.3-fold higher, respectively, in HCT116/BR cells compared with HCT116/PT cells. The protein expression of drug efflux pumps, such as P-glycoprotein (P-gp), breast cancer-resistant protein (BCRP) and the multidrug resistance associated protein 1 (MRP1), did not differ between HCT116/PT and HCT116/BR cells. The expression level of the anti-apoptotic Bcl-xL protein was increased while those of pro-apoptotic Bax and Bim proteins were reduced in HCT116/BR cells. There were no significant differences in cell motility and invasion. This study suggests that exposure of colon cancer cells to butyrate results in development of resistance to butyrate, which may play a role in the acquisition of chemoresistance in colon cancer. IntroductionColon cancer is one of the most common cancers and its prevalence is increasing gradually due to changes in lifestyle (1).Epidemiological studies have attempted to elucidate an association between a high-fiber diet and decreased incidence and progression of colon cancer. Butyrate is a short-chain fatty acid that is naturally produced by the intestinal microflora during dietary fiber fermentation and has been suggested as a target for colon cancer therapy because it inhibits cell proliferation and causes apoptosis in colon cancer cells (2). Butyrate suppresses cell proliferation by causing cell cycle arrest at the G 1 and G 2 phases, which involves cyclin D1 and retinoblastoma (Rb) signaling (3). In addition, butyrate is a histone deacetylase (HDAC) inhibitor, similar to trichostatin A(TSA), and results in apoptosis by increasing the expression of pro-apoptotic proteins, such as Bak, Bad and Bim, and decreasing that of anti-apoptotic proteins, such as Bcl-2 and Bcl-xL (4).Butyrate plays an important role in normal colonocytes as a major energy source and promotes their proliferation (5). However, most cancer cells prefer to utilize glucose as an energy source even under abundant oxygen conditions, so colon cancer cells cannot use butyrate efficiently, which enhances its anticancer effects (6).Recently, it has been reported that butyrate may trigger resistance in colon cancer cells (7). As mentioned above, butyrate is a natural product of dietary fiber fermentation to which colonocytes are c...

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Anti-Proliferative Effect of Naringenin through p38-Dependent Downregulation of Cyclin D1 in Human Colorectal Cancer Cells

Cited by 50 publications

References 37 publications

Cytotoxic Potential and Molecular Pathway Analysis of Silver Nanoparticles in Human Colon Cancer Cells HCT116

Cytotoxic Potential and Molecular Pathway Analysis of Silver Nanoparticles in Human Colon Cancer Cells HCT116

Naringenin-Mediated ATF3 Expression Contributes to Apoptosis in Human Colon Cancer

Butyrate-mediated acquisition of chemoresistance by human colon cancer cells

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