Xie Jing, Cheng Chien-Shan, Zhu Xiao Yan, Shen Ye Hua, Song Li Bin, Chen Hao, Chen Zhen, Liu Lu Ming, Meng Zhi Qiang
Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, P. R. China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P. R. China.
Aging (Albany NY). 2019 May 8;11(9):2681-2698. doi: 10.18632/aging.101940.
The aim of this study was to identify the function of the Mg transporter protein solute carrier family 41 member 1 SLC41A1 in pancreatic ductal adenocarcinoma and the underlying mechanisms. A total of 27 solute carrier proteins were differentially expressed in pancreatic ductal adenocarcinoma. Three of these proteins were correlated with clinical outcomes in patients, among which SLC41A1 was downregulated in tumour. Overexpression of SLC41A1 suppressed orthotopic tumour growth in a mouse model and reduced the cell proliferation, colony formation, and invasiveness of KP3 and Panc-1 cells, which may have been associated with the increased population of apoptotic-prone cells. Overexpression of SLC41A1 reduced the mitochondrial membrane potential, induced Bax while suppressed Bcl-2 expression. Suppression of Bax abrogated the tumour-suppressive effects of SLC41A1. Furthermore, overexpression of SLC41A1 promoted Mg efflux and suppressed Akt/mTOR activity, which is the upstream regulator of Bax and Bcl-2. An increase in Akt activity and supplementation with Mg abolished SLC41A1-induced tumour suppression. The results of this study suggest that SLC41A1 may be a potential target for the treatment of pancreatic ductal adenocarcinoma.
本研究旨在确定镁转运蛋白溶质载体家族41成员1（SLC41A1）在胰腺导管腺癌中的功能及潜在机制。共有27种溶质载体蛋白在胰腺导管腺癌中差异表达。其中三种蛋白与患者的临床结局相关，其中SLC41A1在肿瘤中表达下调。SLC41A1的过表达抑制了小鼠模型中的原位肿瘤生长，并降低了KP3和Panc-1细胞的增殖、集落形成和侵袭能力，这可能与易凋亡细胞数量增加有关。SLC41A1的过表达降低了线粒体膜电位，诱导了Bax表达，同时抑制了Bcl-2表达。抑制Bax可消除SLC41A1的肿瘤抑制作用。此外，SLC41A1的过表达促进了镁外流，并抑制了Akt/mTOR活性，而Akt/mTOR是Bax和Bcl-2的上游调节因子。Akt活性增加和补充镁可消除SLC41A1诱导的肿瘤抑制作用。本研究结果表明，SLC41A1可能是治疗胰腺导管腺癌的潜在靶点。
