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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.
Highlights
Colorectal cancer (CRC) is one of the most common cancers and cause of cancer death in developed countries, highlighting the need of novel strategies for prevention/ therapy of colorectal cancer (CRC) [1].Short chain fatty acids (SCFA), namely acetate, propionate and butyrate are produced by bacterial fermentation of dietary fiber that escape absorption in the small intestine
We tested the inhibition of acetate transport using inhibitors of monocarboxylate transporters such as cyano-4-hydroxycinnamic acid (CHC) [18, 19], DIDS [20] and AR-C155858 [21] (Figure 1c)
Our results showed that Carbonyl cyanide m-chlorophenyl hydrazone (CCCP) inhibited significantly acetate transport in both HCT-15 (71%) and RKO (52%) cells; monensin inhibited acetate uptake in HCT15 (78%) and RKO (36%), and valinomycin presented only a small inhibitory effect in both cell lines (22% and 21% in in HCT-15 and RKO cells, respectively)
Summary
Short chain fatty acids (SCFA), namely acetate, propionate and butyrate are produced by bacterial fermentation of dietary fiber that escape absorption in the small intestine. These compounds are produced in a millimolar ratio of approximately 60:20:20, respectively [2], being a major source of energy for colonocytes. It was shown that in vivo administration of Propionibacterium freudenreichii significantly increased apoptosis in colon cells damaged with a carcinogenic agent (1,2-dimethylhydrazine) without affecting the survival of healthy normal colonocytes [3, 4]. We showed that acetate inhibits CRC cell proliferation, induces apoptosis, promotes lysosomal membrane permeabilization with release of cathepsin D, which is associated with an autophagyindependent degradation of damaged mitochondria [5, 9]. The reason for acetate selectivity towards transformed colon cells without affecting normal colon cells is still elusive
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