Dataset Information

PES1 promotes BET inhibitors resistance and cells proliferation through increasing c-Myc expression in pancreatic cancer.

ABSTRACT: BACKGROUND:Overexpressed PES1 promotes carcinogenesis in various types of malignant tumors. However, the biological role and clinical significance of PES1 in pancreatic cancer are still unexplored. METHODS:The expression level of PES1 in pancreatic cancer cell lines and pancreatic cancer patient samples was determined using Western Blotting analysis, RT-qPCR analysis, immunohistochemical (IHC) analysis of tissue microarray, and the GEPIA web tool. MTS assay, colony formation assay, and xenograft tumor assay were used to evaluate the tumor growth ability of pancreatic cancer cells. RESULTS:We established that the expression of PES1 was abnormally increased in pancreatic cancer tissues and led to poor prognosis of pancreatic cancer patients. We also found that PES1 was responsible for promoting cell growth and contributed to bromodomain and cancer cell resistance to extra-terminal (BET) inhibitors in pancreatic cancer. Furthermore, we showed that PES1 interacted with BRD4 to enhance c-Myc expression, which is the primary cause of cancer cell resistance to BET inhibitors in pancreatic cancer. Finally, CDK5 inhibitors were proven to destabilize PES1 and overcome cancer cell resistance to BET inhibitors in pancreatic cancer cells. CONCLUSIONS:We have shown that PES1 could be one of the promoting factors of tumor growth and a prognosis-related protein of pancreatic cancer. Targeting PES1 with CDK5 inhibitors might help overcome cancer cell resistance to BET inhibitors in pancreatic cancer cells.

SUBMITTER: Jin X

PROVIDER: S-EPMC6852745 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

PES1 promotes BET inhibitors resistance and cells proliferation through increasing c-Myc expression in pancreatic cancer.

Jin Xin X Fang Rui R Fan Ping P Zeng Lipeng L Zhang Bin B Lu Xiaoming X Liu Tao T

Journal of experimental & clinical cancer research : CR 20191112 1

<h4>Background</h4>Overexpressed PES1 promotes carcinogenesis in various types of malignant tumors. However, the biological role and clinical significance of PES1 in pancreatic cancer are still unexplored.<h4>Methods</h4>The expression level of PES1 in pancreatic cancer cell lines and pancreatic cancer patient samples was determined using Western Blotting analysis, RT-qPCR analysis, immunohistochemical (IHC) analysis of tissue microarray, and the GEPIA web tool. MTS assay, colony formation assay ...[more]

PMID: 31718704

Similar Datasets

Project description:BackgroundThe bromodomain and extra-terminal domain (BET) inhibitor is a type of anti-tumor agent, currently being evaluated in phase I and II clinical trials for cancer therapy. It can decrease MYC expression levels and cause effective anti-tumor effects in diverse human cancers. However, its cytotoxic effect and related mechanisms of drug resistance are poorly understood in hepatocellular carcinomas (HCC). Here, we investigated the anti-tumor effects of BET inhibitor on HCC and the molecular mechanisms involved in its associated drug resistance.MethodsWe assessed the cytotoxicity of BET inhibitor on HCC cells compared with sorafenib by cell viability assay, metastasis assay and reproduced the anti-tumor effect in xenograft mouse model. In addition, the molecular mechanisms involved in drug resistance on JQ1-resistant HCC cells were revealed by western blotting, qRT-PCR, whole exome-sequencing and gene-editing technology. Finally, with specific inhibition of EGFR or ERK activity by interference RNAs or inhibitors, the efficacy of the synergistic treatment was investigated using cell viability assay, colony formation, apoptosis and xenograft mouse model.ResultsWe found that JQ1, a commonly used BET bromo-domain inhibitor, offered a better anti-tumor response than sorafenib in MYC-positive HCC cells by inducing apoptosis in vitro and in vivo. Unlike sorafenib, JQ1 treatment significantly impaired mitochondrial respiration and glycolysis in HCC cells. Importantly, we revealed that MAPK activation by a previously undescribed activating mutation of EGFR-I645L, was critical for JQ1 sensitivity through stabilizing oncogenic MYC protein in JQ1-resistant HCC cells. Inhibition of either EGFR or ERK activity overcame the JQ1 resistance and significantly decreased MYC protein level in vitro and in vivo.ConclusionSince MYC amplification is frequently identified in HCC, co-occurring with EGFR amplification, our findings suggest that targeting EGFR signaling might be essential for JQ1 therapy in advanced HCC.

Dataset Information

PES1 promotes BET inhibitors resistance and cells proliferation through increasing c-Myc expression in pancreatic cancer.

Publications

PES1 promotes BET inhibitors resistance and cells proliferation through increasing c-Myc expression in pancreatic cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets