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P300 inhibition enhances gemcitabine-induced apoptosis of pancreatic cancer.

ABSTRACT: The transcriptional cofactor p300 has histone acetyltransferase activity (HAT) and has been reported to participate in chromatin remodeling and DNA repair. We hypothesized that targeting p300 can enhance the cytotoxicity of gemcitabine, which induces pancreatic cancer cell apoptosis by damaging DNA. Expression of p300 was confirmed in pancreatic cancer cell lines and human pancreatic adenocarcinoma tissues by western blotting and immunohistochemistry. When pancreatic cancer cells were treated with gemcitabine, p300 was recruited to chromatin within 24 hours, indicating the role in response to DNA damage. When p300 was gene-silenced with siRNA, histone acetylation was substantially reduced and pancreatic cancer cells were sensitized to gemcitabine. The selective p300 HAT inhibitor C646 similarly decreased histone acetylation, increased gemcitabine-induced apoptosis and thus enhanced the cytotoxicity of gemcitabine on pancreatic cancer cells. These findings indicate that p300 contributes to chemo-resistance of pancreatic cancer against gemcitabine and suggest that p300 and its HAT activity may be a potential therapeutic target to improve outcomes in patients with pancreatic cancer.

SUBMITTER: Ono H

PROVIDER: S-EPMC5239476 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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P300 inhibition enhances gemcitabine-induced apoptosis of pancreatic cancer.

Ono Hiroaki H Basson Marc D MD Ito Hiromichi H

Oncotarget 20160801 32

The transcriptional cofactor p300 has histone acetyltransferase activity (HAT) and has been reported to participate in chromatin remodeling and DNA repair. We hypothesized that targeting p300 can enhance the cytotoxicity of gemcitabine, which induces pancreatic cancer cell apoptosis by damaging DNA. Expression of p300 was confirmed in pancreatic cancer cell lines and human pancreatic adenocarcinoma tissues by western blotting and immunohistochemistry. When pancreatic cancer cells were treated wi ...[more]

PMID: 27322077

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent and aggressive form of pancreatic cancer. Gemcitabine (GEM), the first‑line treatment for PDAC, which alleviates symptoms and enhances the quality of life of patients. However, it is prone to lead to the development of drug resistance during treatment. Interferon (IFN)‑γ exhibits antitumor and immunomodulatory properties. The present study aimed to explore the impact of IFN‑γ on the viability, migration and apoptosis of GEM‑resistant pancreatic cancer cells. Firstly, a GEM‑resistant pancreatic cancer cell line, named PANC‑1/GEM, was constructed. Hematoxylin and eosin staining analyzed the cell morphology, whereas reverse transcription‑quantitative PCR (RT‑qPCR) assessed the expression levels of the drug‑resistance genes multidrug resistance‑associated protein (MRP) and breast cancer resistance protein (BCRP). The MTT assay and cell counting techniques were used to determine the appropriate concentration of IFN‑y and its effects on cell viability. The IFN‑γ‑induced apoptosis of PANC‑1/GEM cells was assessed using an Apoptosis Detection Kit, whereas the impact of IFN‑γ on the migration of these cells was evaluated using a wound‑healing assay. The MTT assay revealed a resistance index of 22.4 in the PANC‑1/GEM cell line. RT‑qPCR indicated that, compared with in wild‑type cells, the PANC‑1/GEM resistant strain exhibited lower MRP and higher BCRP mRNA expression levels. The optimal concentration of IFN‑γ for affecting PANC‑1/GEM cells was determined to be 0.3 µg/ml. At this concentration, IFN‑γ induced PANC‑1/GEM cell apoptosis, along with a notable reduction in migration. Following treatment of PANC‑1/GEM cells with IFN‑γ, MRP expression increased whereas BCRP mRNA expression decreased, indicating a reversal in their drug‑resistance gene expression. In conclusion, IFN‑γ exhibited antitumor immune properties by upregulating MRP and downregulating BCRP expression, reversing drug‑resistance gene expression, and reducing cell viability and migration, while promoting apoptosis in PANC‑1/GEM cells. IFN‑γ could potentially serve as a treatment option for patients with GEM‑resistant pancreatic cancer.

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P300 inhibition enhances gemcitabine-induced apoptosis of pancreatic cancer.

Publications

P300 inhibition enhances gemcitabine-induced apoptosis of pancreatic cancer.

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