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Published on: November 27, 2016
Characterization of acetate transport in colorectal cancer cells and potential therapeutic implications
Suellen Ferro1,2, João Azevedo-Silva1, Margarida Casal1
1CBMA- Centre of Molecular and Environmental Biology, Department of Biology, University of Minho, Campus de Gualtar, Braga, Portugal.
Abstract:
Acetate, together with other short chain fatty acids has been implicated in colorectal cancer (CRC) prevention/therapy. Acetate was shown to induce apoptosis in CRC cells. The precise mechanism underlying acetate transport across CRC cells membrane, that may be implicated in its selectivity towards CRC cells, is not fully understood and was addressed here. We also assessed the effect of acetate in CRC glycolytic metabolism and explored its use in combination with the glycolytic inhibitor 3-bromopyruvate (3BP). We provide evidence that acetate enters CRC cells by the secondary active transporters MCT1 and/or MCT2 and SMCT1 as well as by facilitated diffusion via aquaporins. CRC cell exposure to acetate upregulates the expression of MCT1, MCT4 and CD147, while promoting MCT1 plasma membrane localization. We also observed that acetate increases CRC cell glycolytic phenotype and that acetate-induced apoptosis and anti-proliferative effect was potentiated by 3BP. Our data suggest that acetate selectivity towards CRC cells might be explained by the fact that aquaporins and MCTs are found overexpressed in CRC clinical cases. Our work highlights the importance that acetate transport regulation has in the use of drugs such as 3BP as a new therapeutic strategy for CRC.
Insights
Acetate enters colorectal cancer (CRC) cells via specific transporters, influencing their metabolism and enhancing apoptosis. Combining acetate with 3-bromopyruvate (3BP) shows potential for CRC therapy.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Short-chain fatty acids, including acetate, are linked to colorectal cancer (CRC) prevention and therapy.
- Acetate has demonstrated the ability to induce apoptosis in CRC cells.
- The exact mechanisms of acetate transport in CRC cells and its role in CRC metabolism require further elucidation.
Purpose of the Study:
- To investigate the mechanisms of acetate transport across colorectal cancer cell membranes.
- To assess the impact of acetate on CRC glycolytic metabolism.
- To explore the combined therapeutic potential of acetate and 3-bromopyruvate (3BP) in CRC.
Main Methods:
- Investigated acetate transport using secondary active transporters (MCT1, MCT2, SMCT1) and facilitated diffusion via aquaporins.
- Analyzed the effect of acetate on CRC cell expression of MCT1, MCT4, and CD147.
- Assessed acetate's influence on CRC cell glycolysis and apoptosis, including combination therapy with 3BP.
Main Results:
- Acetate enters CRC cells via MCT1/MCT2, SMCT1, and aquaporins.
- Acetate exposure upregulates MCT1, MCT4, and CD147 expression and promotes MCT1 plasma membrane localization in CRC cells.
- Acetate enhances CRC cell glycolysis, and its apoptosis-inducing and anti-proliferative effects are potentiated by 3BP.
Conclusions:
- Acetate transport mechanisms, including aquaporins and MCTs, are likely involved in its selectivity towards CRC cells due to their overexpression in clinical cases.
- Acetate influences CRC cell metabolism and apoptosis, suggesting a role in CRC therapy.
- Targeting acetate transport, in combination with glycolytic inhibitors like 3BP, represents a promising therapeutic strategy for colorectal cancer.
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