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Synergy between arsenic trioxide and JQ1 on autophagy in pancreatic cancer

Abstract

Pancreatic cancer is a deadliest type of malignancy and lacks effective intervention. We here report a potential strategy for treatment of this malignancy by the combination of arsenic trioxide (ATO) and BET bromodomain inhibitor JQ1. These two agents synergistically modulate multistages of autophagy and thus induce apoptosis effectively in pancreatic cancer cells. Our genomic and biochemical data have demonstrated that crosstalks between ER stress and autophagy play crucial roles during ATO-induced apoptosis, in which NRF2 may stand at the crossroad between cell death and survival. This has been further strengthened by our finding that NRF2 depletion renders insensitive cells into sensitive ones in regard to ATO treatment-caused cell death. The knockdown of NRF2 and the addition of JQ1 result in similar molecular/cellular effects in promoting effective ATO-induced apoptosis in cells that are insensitive to ATO treatment alone. Thus, the combination of ATO and JQ1 may represent a new treatment strategy for pancreatic cancer.

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Data availability

The raw data of the microarray data have been deposited in Gene Expression Omnibus under GEO: GES124069.

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Acknowledgements

We thank HF and Yifen Tang (Ruijin Hospital, affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University), for their supports on many aspects.

Financial support

This study is supported in part by the National Natural Science Foundation (no. 81370655), and by Distinguished Professorship (JZ) from Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University.

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Correspondence to Ji Zhang.

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Xu, C., Wang, X., Zhou, Y. et al. Synergy between arsenic trioxide and JQ1 on autophagy in pancreatic cancer. Oncogene 38, 7249–7265 (2019). https://doi.org/10.1038/s41388-019-0930-3

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