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Oncogene. 2019 Aug 16. doi: 10.1038/s41388-019-0930-3. [Epub ahead of print]

Synergy between arsenic trioxide and JQ1 on autophagy in pancreatic cancer.

Author information

1
State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Rui-Jin Hospital Affiliated to School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
2
Key Laboratory of Molecular Medicine, Ministry of Education, Department of Systems Biology for Medicine, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, 200032, Shanghai, China.
3
Department of Orthopedics, Civil Aviation Hospital of Shanghai, Shanghai, China.
4
Fujian Key Laboratory for Prenatal Diagnosis and Birth Defect, Fujian Provincial Maternity and Children's Hospital, affiliated hospital of Fujian Medical University, FuZhou, 350001, FuJian, China.
5
State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Rui-Jin Hospital Affiliated to School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Zj11222@rjh.com.cn.

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.

PMID:
31420604
DOI:
10.1038/s41388-019-0930-3

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