<i>Se</i>-Allylselenocysteine induces autophagy by modulating the AMPK/mTOR signaling pathway and epigenetic regulation of PCDH17 in human colorectal adenocarcinoma cells

Wu, Juan; Wang, Fang Zong; Tsai, Mei Ling; Lo, Chih Yu; Badmaev, Vladimir; Ho, Chi Tang; Wang, Ying Jan; Pan, Min‐Hsiung

doi:10.1002/mnfr.201500373

Cited by 44 publications

(34 citation statements)

References 42 publications

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“…Interestingly, we also identified that AMPK signaling is responsible for NP-induced mTOR inhibition in SCs. AMPK has been shown to dephosphorylate TSC2, which inhibits mTOR activity and stimulates autophagy (Tanwar et al 2012;Wu et al 2015;Xu et al 2014). As in our study, specifically inducing activation of AMPK with AICAR further decreased the phosphorylation of TSC2 in NP-treated SCs, whereas pharmacological blockade and siRNA-mediated knockdown of AMPK inhibited it.…”

Section: Discussionsupporting

confidence: 78%

“…AMPK-regulated mTOR signaling pathway has been suggested to be one of the master regulators of autophagy (Wu et al 2015;Yamamoto et al 2014). We next investigated whether NP induces autophagy through modulation of AMPK-mTOR pathway in testis.…”

Section: Np Triggers Activation Of Ampkα-tsc2-mtor-p70s6k/4ebp1 Signamentioning

confidence: 99%

“…The AMPK inhibitor Compound C counteracts the effects of NP on AMPK-mTOR signaling pathway and autophagy Since AMPK is a major negative regulator of mTOR pathway (Wu et al 2015), we further studied whether NP-induced AMPK activation leads to inhibition of mTOR signaling as well as up-regulation of autophagy in SCs. Firstly, we studied the effect of Compound C, an antagonist of the AMPK signaling pathway.…”

Section: Np Triggers Activation Of Ampkα-tsc2-mtor-p70s6k/4ebp1 Signamentioning

confidence: 99%

“…Intriguingly, abundant studies have demonstrated that AMPK has the ability to stimulate autophagy by inhibiting the mTOR signaling via phosphorylation of the tuberous sclerosis complex 2 (TSC2) (Wu et al 2015). Additionally, previous study of Tanwar et al has suggested that aberrant AMPK-mTOR signaling causes disruption of SC polarity and spermatogenesis (Tanwar et al 2012).…”

Section: Introductionmentioning

confidence: 99%

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4-Nonylphenol induces autophagy and attenuates mTOR-p70S6K/4EBP1 signaling by modulating AMPK activation in Sertoli cells

Duan

Quan

et al. 2017

Toxicology Letters

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The estrogenic chemical 4-nonylphenol (NP) is known to impair testicular devolopment and spermatogenesis in rodents. The objective of this study was to explore the effects of NP on autophagy induction and AMPK-mTOR signaling pathway in Sertoli cells (SCs), which are the "nursemaid cells" for meiosis of spermatocytes. In this study we exposed 7-week-old male rats to NP by intra-peritoneal injection at 0, 20, 50 or 100 mg/kg body weight/2 days for 20 consecutive days. Our results showed that exposure to NP dose-dependently induces the formation of autophagosomes in SCs, increases the expression of Beclin-1, the conversion of LC3-I to LC3-II and the mRNA expression of Atg3, Atg5, Atg7 and Atg12 in testis, and these effects are concomitant with the activation of AMPK, and the suppression of TSC2-mTOR-p70S6K/4EBP1 signaling cascade in testis. Furthermore, 10 µM Compound C or AMPKα1 siRNA pre-treatment effectively attenuated autophagy and reversed AMPK-mTOR-p70S6K/4EBP1 signaling in NP-treated SCs. Co-treatment with 1 mM AICAR remarkably strengthened NP-induced autophagy and mTOR inhibition in SCs. Together, these data suggest that NP stimulates Sertoli cell autophagy and inhibits mTOR-p70S6K/4EBP1 activity through AMPK activation, which is the potential mechanism responsible for the regulation of testis function and differentiation following NP exposure.

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Section: Discussionsupporting

confidence: 78%

Section: Np Triggers Activation Of Ampkα-tsc2-mtor-p70s6k/4ebp1 Signamentioning

confidence: 99%

Section: Np Triggers Activation Of Ampkα-tsc2-mtor-p70s6k/4ebp1 Signamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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4-Nonylphenol induces autophagy and attenuates mTOR-p70S6K/4EBP1 signaling by modulating AMPK activation in Sertoli cells

Duan

Quan

et al. 2017

Toxicology Letters

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“…The fact that PMFs increase TIMPs and decrease MMPs suggests that PMFs possess antimetastasis properties. In particular, protocadherins 17 (PCDH17) exhibited anticancer cell growth and antimetastasis activities by inducing PCD and regulating the cell cycle . In this study, we found that PMFs restored the substantially decreased PCDH17 level in the B a P/DSS‐induced tumorigenesis model.…”

Section: Resultsmentioning

confidence: 65%

Polymethoxyflavones prevent benzo[a]pyrene/dextran sodium sulfate‐induced colorectal carcinogenesis through modulating xenobiotic metabolism and ameliorate autophagic defect in ICR mice

Tsai

Lai

et al. 2017

Intl Journal of Cancer

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Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental carcinogenic pollutants and they have become an important issue in food contamination. Dietary intake of PAHs has been recognized as a major route of human exposure. However, the mechanisms behind dietary PAH-induced colorectal cancer (CRC) remain unclear. Several studies have shown that polymethoxyflavones (PMFs) are effective in preventing carcinogen-induced CRC or colitis. In this study, we investigated the preventive effect of PMFs on benzo[a]pyrene/dextran sulfate sodium (BaP/DSS)-induced colorectal tumorigenesis in ICR mice. We found that PMFs significantly prevented BaP/DSS-induced colorectal tumor formation. BaP mutagenic metabolite and DNA adducts were found to be reduced in colonic tissue in the PMFs-treated groups through the modulation of BaP metabolism. At the molecular level, the results of RNA-sequencing indicated that PMFs ameliorated BaP/DSS-induced abnormal molecular mechanism change including activated inflammation, downregulated anti-oxidation targets, and induced metastasis genes. The autophagic defect caused by BaP/DSS-induced tumorigenesis was improved by pretreatment with PMFs. We found BaP/DSS-induced CRC may be a Wnt/β-catenin independent process. Additionally, consumption of PMFs extracts also altered the composition of gut microbiota and made it similar to that in the control group by increasing butyrate-producing probiotics and decreasing CRC-related bacteria. BaP in combination with DSS significantly induced colorectal tumorigenesis through induced DNA adduct formation, abnormal gene expression, and imbalanced gut microbiota composition. PMFs were a powerful preventive agent that suppressed BaP/DSS-induced CRC via modulating multiple pathways as well as ameliorating autophagic defect. These results demonstrated for the first time the chemopreventive efficacy and comprehensive mechanisms of dietary PMFs for preventing BaP/DSS-induced colorectal carcinogenesis.

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Induction of autophagic cell death in human ovarian carcinoma cells by Antrodia salmonea through increased reactive oxygen species generation

Yang

Lin

Karuppaiya

et al. 2018

Journal Cellular Physiology

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We reported in our previously executed studies that the fermented culture broth of Antrodia salmonea (AS), a mushroom used in Taiwanese folk medicine induced reactive oxygen species (ROS)‐mediated apoptosis in human ovarian carcinoma cells. In this study, we studied the anticancer efficacies of AS (0–240 μg/ml) by examining the key molecular events implicated in cell death associated with autophagy in SKOV‐3 and A2780 human ovarian carcinoma cells and clarified the fundamental molecular mechanisms. Treatment of ovarian carcinoma cells with AS‐induced autophagic cell death mediated by increased microtubule‐associated protein LC3‐II, GFP‐LC3 puncta, and acidic vesicular organelle (AVO) formation. These events are linked with the activation of p62/SQSTM1, the inhibition of ATG4B, the expression of ATG7, and the dysregulation of Beclin‐1/Bcl‐2 (i.e., B‐cell lymphoma 2). N‐acetylcysteine inhibited AS‐induced ROS generation, which in turn constricted AS‐induced LC3 conversion, AVO formation, and ATG4B inhibition, indicating ROS‐mediated autophagy cell death. In addition, the 3‐methyladenine (3‐MA) or chloroquine (CQ)‐induced autophagy inhibition decreased AS‐induced apoptosis. Additionally, apoptosis inhibition by Z‐VAD‐FMK, a pan‐caspase inhibitor, substantially suppressed AS‐induced autophagy. Furthermore, AS‐inhibited HER‐2/ neu and PI3K/AKT signaling pathways which were reversed by autophagy inhibitors 3‐MA and CQ. Thus, A. salmonea is a potential chemopreventive agent that is capable of activating ROS‐mediated autophagic cell death in ovarian carcinoma cells.

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Se-Allylselenocysteine induces autophagy by modulating the AMPK/mTOR signaling pathway and epigenetic regulation of PCDH17 in human colorectal adenocarcinoma cells

Abstract: These results reveal that ASC is an effective inducer of autophagy through regulating the AMPK/mTOR and PCDH17 expression via epigenetic modification.

Cited by 44 publications

References 42 publications

4-Nonylphenol induces autophagy and attenuates mTOR-p70S6K/4EBP1 signaling by modulating AMPK activation in Sertoli cells

4-Nonylphenol induces autophagy and attenuates mTOR-p70S6K/4EBP1 signaling by modulating AMPK activation in Sertoli cells

Polymethoxyflavones prevent benzo[a]pyrene/dextran sodium sulfate‐induced colorectal carcinogenesis through modulating xenobiotic metabolism and ameliorate autophagic defect in ICR mice

Induction of autophagic cell death in human ovarian carcinoma cells by Antrodia salmonea through increased reactive oxygen species generation

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