This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Research
Antitumor effects of lactate transport inhibition on esophageal adenocarcinoma cells
Eduardo Chueca
Centro de Investigacion Biomedica en red en Bioingenieria Biomateriales y Nanomedicina
Corresponding Author
ORCiD: https://orcid.org/0000-0003-3644-9240
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
As a consequence of altered glucose metabolism, cancer cells intake is increased, producing large amounts of lactate which is pumped out the cytosol by monocarboxylate transporters (MCTs).
MCTs are frequently overexpressed in tumors, MCT1 in the well oxygenated areas and MCT4 in hypoxic regions, and recent evidence has reported that MCT inhibition can exert antineoplastic effects, but this aspect has not been investigated in esophageal adenocarcinoma (EAC) yet. In the present study, MCT1 and MCT4 levels were assessed in EAC cells and the effects of MCT-1 selective inhibitor AZD3965, hypoxia and a glucose overload were evaluated in vitro .
Methods
Two EAC cell lines (OE33 and OACM5.1C) were treated with different concentrations of AZD3965 (10-100nM) in the presence or absence of a glucose overload under normoxic or hypoxic conditions and parameters of cytotoxicity, oxidative stress, intracellular pH (pHi) and lactate levels were evaluated.
Results
MCT1 was present in both cell lines whereas MCT4 was expressed in OE33 cells and only in a small population of the metastatic 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 NHE-1 expression on these cells.
Conclusion
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.
Keywords
Esophageal adenocarcinoma, MCT, lactate, intracellular pH, proton transport, hypoxia, glucose, apoptosis, proliferation
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 28 Sep, 2020
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Cellular Metabolism
Learn more about our company.
This is a preprint. It has not completed peer review.
Research
Antitumor effects of lactate transport inhibition on esophageal adenocarcinoma cells
Eduardo Chueca
Centro de Investigacion Biomedica en red en Bioingenieria Biomateriales y Nanomedicina
Corresponding Author
ORCiD: https://orcid.org/0000-0003-3644-9240
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 28 Sep, 2020
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Cellular Metabolism
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
As a consequence of altered glucose metabolism, cancer cells intake is increased, producing large amounts of lactate which is pumped out the cytosol by monocarboxylate transporters (MCTs).
MCTs are frequently overexpressed in tumors, MCT1 in the well oxygenated areas and MCT4 in hypoxic regions, and recent evidence has reported that MCT inhibition can exert antineoplastic effects, but this aspect has not been investigated in esophageal adenocarcinoma (EAC) yet. In the present study, MCT1 and MCT4 levels were assessed in EAC cells and the effects of MCT-1 selective inhibitor AZD3965, hypoxia and a glucose overload were evaluated in vitro .
Methods
Two EAC cell lines (OE33 and OACM5.1C) were treated with different concentrations of AZD3965 (10-100nM) in the presence or absence of a glucose overload under normoxic or hypoxic conditions and parameters of cytotoxicity, oxidative stress, intracellular pH (pHi) and lactate levels were evaluated.
Results
MCT1 was present in both cell lines whereas MCT4 was expressed in OE33 cells and only in a small population of the metastatic 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 NHE-1 expression on these cells.
Conclusion
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.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8