SAHA down-regulates the expression of indoleamine 2,3-dioxygenase via inhibition of the JAK/STAT1 signaling pathway in gallbladder carcinoma cells

Zhang, Peng; Jiang, Guanmin; Gao, Junying; Li, Lingling; Du, Jie; Jiao, Xingyuan

doi:10.3892/or.2012.2073

Cited by 11 publications

(9 citation statements)

References 30 publications

(27 reference statements)

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“…STAT3 (signal transducer and activator of transcription 3) plays a key role in generation of tolerogenic DCs, and acetylated STAT3 (acetylation site, Lys 685 ) moves to the nucleus and acts as a transcription factor on IDO1 promoter to induce expression [25, 26]. This transcriptional activity can be abrogated with JSI124, an inhibitor of the biological activity of acetyl-STAT3.…”

Section: Resultsmentioning

confidence: 99%

Slc5a8, a Na+-coupled high-affinity transporter for short-chain fatty acids, is a conditional tumour suppressor in colon that protects against colitis and colon cancer under low-fibre dietary conditions

Gurav

Sivaprakasam

Bhutia

et al. 2015

Biochemical Journal

124

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Summary Mammalian colon harbors trillions of bacteria under physiologic conditions; this symbiosis is made possible because of a tolerized response from the mucosal immune system. The mechanisms underlying this tolerogenic phenomenon remain poorly understood. Here we show that Slc5a8, a Na+-coupled high-affinity transporter in colon for the bacterial fermentation product butyrate, plays a critical role in this process. Among various immune cells in colon, dendritic cells (DCs) are unique not only in their accessibility to luminal contents but also in their ability to induce tolerogenic phenotype in T cells. We found that DCs exposed to butyrate express the immunosuppressive enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and aldehyde dehydrogenase 1A2 (Aldh1A2), promote conversion of naïve T cells into immunosuppressive FoxP3+ Tregs, and suppress conversion of naïve T cells into pro-inflammatory IFN-γ-producing cells. Slc5a8-null DCs do not induce IDO1 and Aldh1A2 and do not generate Tregs or suppress IFN-γ-producing T cells in response to butyrate. We also provide in vivo evidence for an obligatory role for Slc5a8 in suppression of IFN-γ-producing T cells. Furthermore, Slc5a8 protects against colitis and colon cancer under conditions of low-fiber intake but not when dietary fiber intake is optimal. This agrees with the high-affinity nature of the transporter to mediate butyrate entry into cells. We conclude that Slc5a8 is an obligatory link between dietary fiber and mucosal immune system via the bacterial metabolite butyrate, and that this transporter is a conditional tumor suppressor in colon linked to dietary fiber content.

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Section: Resultsmentioning

confidence: 99%

Slc5a8, a Na+-coupled high-affinity transporter for short-chain fatty acids, is a conditional tumour suppressor in colon that protects against colitis and colon cancer under low-fibre dietary conditions

Gurav

Sivaprakasam

Bhutia

et al. 2015

Biochemical Journal

124

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“…Phosphorylated STAT1 forms a homodimer in the cytoplasm, and then it is transferred to the nucleus and binds to interferon γ-activated sequence (GAS) and stimulates the expression of interferon γ-induced genes. Interferon γ signaling can also lead to the phosphorylation STAT3 that binds to the GAS element and induces expression of inflammatory genes [ 94 – 96 ]. During inflammation, reactive oxygen and nitrogen species are produced to fight pathogens, but these chemicals can also destroy DNA, which in turn can initiate mutations and promote cancer [ 97 ].…”

Section: Helicobacter Outer Membrane Proteins and Gastric Cancermentioning

confidence: 99%

Molecular Mechanism of Helicobacter pylori-Induced Gastric Cancer

Alipour

2020

J Gastrointest Canc

150

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Introduction Various types of cancers threaten human life. The role of bacteria in causing cancer is controversial, but it has been determined that the Helicobacter pylori infection is one of the identified risk factors for gastric cancer. Helicobacter pylori infection is highly prevalent, and about half of the world , s population is infected with it. Objective The aim of this study was the role of Helicobacter pylori in the development of gastric cancer. Method We obtained information from previously published articles. Results and Conclusion The bacterium has various virulence factors, including cytotoxin-associated gene A, vacuolating cytotoxin A, and the different outer membrane proteins that cause cancer by different mechanisms. These virulence factors activate cell signaling pathways such as PI3-kinase/Akt, JAK/STAT and Ras, Raf, and ERK signaling that control cell proliferation. Uncontrolled proliferation can lead to cancer.

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“…Protein extraction and Western blotting were performed as we described previously [ 16 ]. Briefly, cells were washed three times with ice-cold phosphate buffer and lysed in a lysis buffer.…”

Section: Methodsmentioning

confidence: 99%

“…Gallbladder carcinoma is the fifth most commonly diagnosed gastrointestinal malignancy worldwide and the most aggressive malignant neoplasm of the biliary tract [ 1 – 2 ]. Mainly due to its non-specific symptoms and highly invasive nature, most patients are diagnosed at an advanced stage, with only 20%-40% of patients suitable for curative resection [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Histone Deacetylase Inhibitors Inhibit the Proliferation of Gallbladder Carcinoma Cells by Suppressing AKT/mTOR Signaling

Zhang

Guo

et al. 2015

PLoS ONE

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Gallbladder carcinoma is an aggressive malignancy with high mortality mainly due to the limited potential for curative resection and its resistance to chemotherapeutic agents. Here, we show that the histone deacetylase inhibitors (HDACIs) trichostatin-A (TSA) and suberoylanilide hydroxamic acid (SAHA) reduce the proliferation and induce apoptosis of gallbladder carcinoma cells by suppressing the AKT/mammalian target of rapamycin (mTOR) signaling. Gallbladder carcinoma SGC-996 cells were treated with different concentrations of TSA and SAHA for different lengths of time. Cell proliferation and morphology were assessed with MTT assay and microscopy, respectively. Cell cycle distribution and cell apoptosis were analyzed with flow cytometry. Western blotting was used to detect the proteins related to apoptosis, cell cycle, and the AKT/mTOR signaling pathway. Our data showed that TSA and SAHA reduced SGC-996 cell viability and arrested cell cycle at the G1 phase in a dose- and time-dependent manner. TSA and SAHA promoted apoptosis of SGC-996 cells, down-regulated the expression of cyclin D1, c-Myc and Bmi1, and decreased the phosphorylation of AKT, mTOR p70S6K1, S6 and 4E-BP1. Additionally, the mTOR inhibitor rapamycin further reduced the cell viability of TSA- and SAHA-treated SGC-996 cells and the phosphorylation of mTOR, whereas the mTOR activator 1,2-dioctanoyl-sn-glycero-3-phosphate (C8-PA) exerted the opposite influence. Our results demonstrate that histone deacetylase inhibitors (HDACIs) suppress the proliferation of gallbladder carcinoma cell via inhibition of AKT/mTOR signaling. These findings offer a mechanistic rationale for the application of HDACIs in gallbladder carcinoma treatment.

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SAHA down-regulates the expression of indoleamine 2,3-dioxygenase via inhibition of the JAK/STAT1 signaling pathway in gallbladder carcinoma cells

Cited by 11 publications

References 30 publications

Slc5a8, a Na+-coupled high-affinity transporter for short-chain fatty acids, is a conditional tumour suppressor in colon that protects against colitis and colon cancer under low-fibre dietary conditions

Slc5a8, a Na+-coupled high-affinity transporter for short-chain fatty acids, is a conditional tumour suppressor in colon that protects against colitis and colon cancer under low-fibre dietary conditions

Molecular Mechanism of Helicobacter pylori-Induced Gastric Cancer

Histone Deacetylase Inhibitors Inhibit the Proliferation of Gallbladder Carcinoma Cells by Suppressing AKT/mTOR Signaling

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