
Downregulation of MCT 4 for lactate exchange promotes the cytotoxicity of NK cells in breast carcinoma
Author(s) -
Long Yaping,
Gao Zihe,
Hu Xiao,
Xiang Feng,
Wu Zhaozhen,
Zhang Jiahui,
Han Xiao,
Yin Liyong,
Qin Junfang,
Lan Lan,
Yin Fuzai,
Wang Yue
Publication year - 2018
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.1713
Subject(s) - cytotoxicity , extracellular , downregulation and upregulation , flow cytometry , autophagy , tumor microenvironment , biology , transfection , microbiology and biotechnology , chemistry , cancer research , cell culture , biochemistry , in vitro , apoptosis , tumor cells , gene , genetics
Monocarboxylate transporter‐4 ( MCT 4), a monocarboxylic acid transporter, demonstrates significantly increased expression in the majority of malignancies. We performed an experiment using BALB /C mice, and our results showed that Sh MCT 4 transfection or the pharmaceutic inhibition of MCT 4 with 7acc1 strengthens the activity of NK cells. The results of a calcein assay revealed that the cytotoxicity of NK cells was strengthened via inhibition of MCT 4. In addition, ELISA testing showed that the content of perforin and CD 107a was increased, and PCR amplification and immunoblotting revealed that the expression of NKG 2D and H60 was upregulated after the inhibition of MCT 4. Further, we observed an elevated pH value, decreased extracellular lactate flow, and attenuated tumor growth. Therefore, we concluded that the inhibition of MCT 4 enhanced the cytotoxicity of NK cells by blocking lactate flux and reversing the acidified tumor microenvironment. In addition to these findings, we also discovered that MCT 4 depletion may have a pronounced impact on autophagy, which was surmised by observing that the inhibition of autophagy (3 MA ) pulled the enhanced cytotoxicity of NK cells downwards. Together, these data suggest that the key effect of MCT 4 depletion on NK cells probably utilizes inductive autophagy as a compensatory metabolic mechanism to minimize the acidic extracellular microenvironment associated with lactate export in tumors.