Key Laboratory of Antibody Technology, National Health Commission, Nanjing Medical University, 101 Longmian Road, Nanjing, 211166, Jiangsu, China.
Jiangsu Province Engineering Research Center of Antibody Drug, Nanjing Medical University, 101 Longmian Road, Nanjing, 211166, Jiangsu, China.
Hum Cell. 2022 Sep;35(5):1464-1474. doi: 10.1007/s13577-022-00731-3. Epub 2022 Jun 24.
Disulfiram (DSF), which is an inhibitor of aldehyde dehydrogenase (ALDH) and approved by the FDA for the treatment of alcoholism previously, has been repurposed for use as a cancer treatment because of its potent effect in preclinical studies. In this study, we found that disulfiram forms potent complexes with copper (DSF/Cu) inhibited cell proliferation, induced apoptosis in human pancreatic cancer cells, which was detected by flow cytometry and western blotting. Meanwhile, autophagy and autophagic flux also clearly observed by transmission electron microscopy, confocal microscopy and flow cytometry. Our results also showed that DSF/Cu induced transcription factor p8 upregulation and PI3K/mTOR signaling pathway activation detected by real-time PCR and western blotting. Additionally, suppression of p8 inactivated the mTOR signaling pathway and autophagic flux maintained. Furthermore, mechanism study indicated that autophagy induced by DSF/Cu was regulated by p8 and was related to PI3K/mTOR/p70S6K signaling pathway in pancreatic cancer cells. Our findings provide insights into the role of p8 in regulating autophagy induced by DSF/Cu effects in pancreatic cancer cells.
双硫仑（DSF），一种以前被 FDA 批准用于治疗酗酒的乙醛脱氢酶（ALDH）抑制剂，由于在临床前研究中的强大效果，已被重新用于癌症治疗。在这项研究中，我们发现双硫仑与铜形成强复合物（DSF/Cu）抑制人胰腺癌细胞增殖，通过流式细胞术和 Western blot 检测到细胞凋亡。同时，透射电子显微镜、共聚焦显微镜和流式细胞术也清楚地观察到自噬和自噬流。我们的结果还表明，DSF/Cu 诱导实时 PCR 和 Western blot 检测到转录因子 p8 的上调和 PI3K/mTOR 信号通路的激活。此外，抑制 p8 可使 mTOR 信号通路失活并维持自噬流。此外，机制研究表明，DSF/Cu 诱导的自噬受 p8 调节，与胰腺癌细胞中的 PI3K/mTOR/p70S6K 信号通路有关。我们的研究结果为 p8 在调节胰腺癌细胞中 DSF/Cu 诱导的自噬中的作用提供了新的见解。
