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Downregulation of MCT4 for lactate exchange promotes the cytotoxicity of NK cells in breast carcinoma.
Long, Yaping; Gao, Zihe; Hu, Xiao; Xiang, Feng; Wu, Zhaozhen; Zhang, Jiahui; Han, Xiao; Yin, Liyong; Qin, Junfang; Lan, Lan; Yin, Fuzai; Wang, Yue.
Afiliação
  • Long Y; School of Medicine, Nankai University, Tianjin, China.
  • Gao Z; School of Medicine, Nankai University, Tianjin, China.
  • Hu X; School of Medicine, Nankai University, Tianjin, China.
  • Xiang F; School of Medicine, Nankai University, Tianjin, China.
  • Wu Z; School of Medicine, Nankai University, Tianjin, China.
  • Zhang J; School of Medicine, Nankai University, Tianjin, China.
  • Han X; School of Medicine, Nankai University, Tianjin, China.
  • Yin L; First Hospital of Qinhuangdao, Qinhuangdao, Hebei, China.
  • Qin J; School of Medicine, Nankai University, Tianjin, China.
  • Lan L; Tianjin Cancer Hospital, Tianjin Medical University, Tianjin, China.
  • Yin F; First Hospital of Qinhuangdao, Qinhuangdao, Hebei, China.
  • Wang Y; School of Medicine, Nankai University, Tianjin, China.
Cancer Med ; 7(9): 4690-4700, 2018 09.
Article em En | MEDLINE | ID: mdl-30051648
ABSTRACT
Monocarboxylate transporter-4 (MCT4), 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 ShMCT4 transfection or the pharmaceutic inhibition of MCT4 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 MCT4. In addition, ELISA testing showed that the content of perforin and CD107a was increased, and PCR amplification and immunoblotting revealed that the expression of NKG2D and H60 was upregulated after the inhibition of MCT4. Further, we observed an elevated pH value, decreased extracellular lactate flow, and attenuated tumor growth. Therefore, we concluded that the inhibition of MCT4 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 MCT4 depletion may have a pronounced impact on autophagy, which was surmised by observing that the inhibition of autophagy (3MA) pulled the enhanced cytotoxicity of NK cells downwards. Together, these data suggest that the key effect of MCT4 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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Células Matadoras Naturais / Regulação Neoplásica da Expressão Gênica / Ácido Láctico / Transportadores de Ácidos Monocarboxílicos / Proteínas Musculares Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Células Matadoras Naturais / Regulação Neoplásica da Expressão Gênica / Ácido Láctico / Transportadores de Ácidos Monocarboxílicos / Proteínas Musculares Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2018 Tipo de documento: Article