College of Life Science, Northeast Forestry University, Harbin, China.
Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China.
J Cell Physiol. 2019 Nov;234(11):20648-20661. doi: 10.1002/jcp.28670. Epub 2019 May 3.
The essential trace element zinc (Zn) is widely required in cellular functions, and abnormal Zn homeostasis causes a variety of health problems including immunodeficiency and sensory dysfunctions. Previous studies had shown that Zn availability was also important for tumor growth and progression. The aim of the present study was to investigate the potential mechanisms of N,N,N,N-Tetrakis(2-pyridylmethyl)-ethylenediamine (TPEN) (a membrane permeable zinc chelator) induced pancreatic cancer cell death. The text of inductively coupled plasma-mass spectrometry (ICP-MS) showed in human pancreatic cancer samples that the zinc content in cancer was higher than that in adjacent tissues. The pancreatic cancer cell lines Panc-1, 8988T, BxPc-3, and L3.6 were used in this study. Our results indicated that TPEN markedly induced cell death, via increasing reactive oxygen species (ROS) and restraining autophagy. Our data also indicated that TPEN-stimulated mitochondrial metabolism produced much ROS. Meanwhile, TPEN reduced the levels of glutathione (GSH) and triggered ROS outbreak, which were the main causes of cell death. In addition, cell autophagy was significantly depressed in Panc-1 cells treated by TPEN, which was due to the ability of disrupting lysosomal by TPEN. Thus, we thought zinc depletion by TPEN was a potential therapeutic strategy for pancreatic cancer.
必需微量元素锌（Zn）广泛存在于细胞功能中，而异常的 Zn 稳态会导致多种健康问题，包括免疫缺陷和感觉功能障碍。先前的研究表明，Zn 的可用性对于肿瘤的生长和进展也很重要。本研究旨在探讨 N,N,N,N-四（2-吡啶甲基）乙二胺（TPEN）（一种膜透性锌螯合剂）诱导胰腺癌细胞死亡的潜在机制。电感耦合等离子体质谱（ICP-MS）的文本显示，在人类胰腺癌样本中，癌症中的锌含量高于相邻组织。本研究使用了胰腺癌细胞系 Panc-1、8988T、BxPc-3 和 L3.6。我们的结果表明，TPEN 通过增加活性氧（ROS）和抑制自噬来显著诱导细胞死亡。我们的数据还表明，TPEN 刺激的线粒体代谢产生了大量的 ROS。同时，TPEN 降低了谷胱甘肽（GSH）的水平并引发了 ROS 的爆发，这是细胞死亡的主要原因。此外，TPEN 处理的 Panc-1 细胞中的细胞自噬明显受到抑制，这是由于 TPEN 破坏溶酶体的能力所致。因此，我们认为 TPEN 耗竭锌是治疗胰腺癌的一种潜在治疗策略。
