State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Rui-Jin Hospital Affiliated to School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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.
Oncogene. 2019 Nov;38(47):7249-7265. doi: 10.1038/s41388-019-0930-3. Epub 2019 Aug 16.
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.
胰腺癌是最致命的恶性肿瘤之一，缺乏有效的干预手段。我们在这里报告了一种通过三氧化二砷（ATO）和 BET 溴结构域抑制剂 JQ1 联合治疗这种恶性肿瘤的潜在策略。这两种药物协同调节自噬的多个阶段，从而有效地诱导胰腺癌细胞凋亡。我们的基因组和生化数据表明，内质网应激和自噬之间的串扰在 ATO 诱导的细胞凋亡过程中起着至关重要的作用，其中 NRF2 可能处于细胞死亡和存活的十字路口。我们的发现进一步证实了这一点，即 NRF2 耗竭使对 ATO 治疗引起的细胞死亡不敏感的细胞对 ATO 治疗变得敏感。敲低 NRF2 并添加 JQ1 可导致类似的分子/细胞效应，从而促进对 ATO 治疗不敏感的细胞中有效的 ATO 诱导凋亡。因此，ATO 和 JQ1 的联合可能代表治疗胰腺癌的一种新策略。
