Antitumor effects of lactate transport inhibition on esophageal adenocarcinoma cells

• Published in: Journal of physiology and biochemistry Vol. 79; no. 1; pp. 147 - 161
• Main Authors: Grasa, Laura, Chueca, Eduardo, Arechavaleta, Samantha, García-González, María Asunción, Sáenz, María Ángeles, Valero, Alberto, Hördnler, Carlos, Lanas, Ángel, Piazuelo, Elena
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01-02-2023; Springer; Springer Nature B.V
• Subjects: Adenocarcinoma; Analysis; Animal Physiology; Anticancer properties; Antineoplastic Agents; Antineoplastic drugs; Antitumor activity; Apoptosis; Biomedical and Life Sciences; Biomedicine; Cancer; Cell proliferation; Cytosol; Cytotoxicity; Dextrose; Esophageal cancer; Esophagus; Evaluation; Glucose; Glucose metabolism; Human Physiology; Humans; Hypoxia; Intracellular; Lactates; Lactic acid; Monocarboxylic Acid Transporters - metabolism; Na+/H+-exchanging ATPase; Original; Original Article; Oxidative stress; Symporters - metabolism; Toxicity; Intracellular pH; Proliferation; Lactate; Esophageal adenocarcinoma; MCT; Apoptosis
• ISSN: 1138-7548; 1877-8755
• DOI: 10.1007/s13105-022-00931-3

As a consequence of altered glucose metabolism, cancer cell intake is increased, producing large amounts of lactate which is pumped out the cytosol by monocarboxylate transporters (MCTs). MCT 1 and MCT4 are frequently overexpressed in tumors, and recently, MCT inhibition has been reported to exert antineoplastic effects. In the present study, MCT1 and MCT4 levels were assessed in esophageal adenocarcinoma (EAC) cells and the effects of the MCT-1 selective inhibitor AZD3965, hypoxia, and a glucose overload were evaluated in vitro. Two EAC cell lines (OE33 and OACM5.1C) were treated with AZD3965 (10–100 nM) under different conditions (normoxia/hypoxia) and also different glucose concentrations, and parameters of cytotoxicity, oxidative stress, intracellular pH (pHi), and lactate levels were evaluated. MCT1 was present in both cell lines whereas MCT4 was expressed in OE33 cells and only in a small proportion of OACM5.1C cells. Glucose addition did not have any effect on apoptosis nor cell proliferation. AZD3965 increased apoptosis and reduced proliferation of OACM5.1C cells, effects which were abrogated when cells were growing in hypoxia. MCT1 inhibition increased intracellular lactate levels in all the cells evaluated, but this increase was higher in cells expressing only MCT1 and did not affect oxidative stress. AZD3965 induced a decrease in pHi of cells displaying low levels of MCT4 and also increased the sodium/hydrogen exchanger 1 (NHE-1) expression on these cells. These data provide in vitro evidence supporting the potential of MCT inhibitors as novel antineoplastic drugs for EAC and highlight the importance of achieving a complete MCT inhibition.