Green tea phenolics inhibit butyrate-induced differentiation of colon cancer cells by interacting with monocarboxylate transporter 1

Abstract

Diet has a significant impact on colorectal cancer and both dietary fiber and plant-derived compounds have been independently shown to be inversely related to colon cancer risk. Butyrate (NaB), one of the principal products of dietary fiber fermentation, induces differentiation of colon cancer cell lines by inhibiting histone deacetylases (HDACs). On the other hand, (−)-epicatechin (EC) and (−)-epigallocatechin gallate (EGCG), two abundant phenolic compounds of green tea, have been shown to exhibit antitumoral properties. In this study we used colon cancer cell lines to study the cellular and molecular events that take place during co-treatment with NaB, EC and EGCG. We found that (i) polyphenols EC and EGCG fail to induce differentiation of colon adenocarcinoma cell lines; (ii) polyphenols EC and EGCG reduce NaB-induced differentiation; (iii) the effect of the polyphenols is specific for NaB, since differentiation induced by other agents, such as trichostatin A (TSA), was unaltered upon EC and EGCG treatment, and (iv) is independent of the HDAC inhibitory activity of NaB. Also, (v) polyphenols partially reduce cellular NaB; and (vi) on a molecular level, reduction of cellular NaB uptake by polyphenols is achieved by impairing the capacity of NaB to relocalize its own transporter (monocarboxylate transporter 1, MCT1) in the plasma membrane. Our findings suggest that beneficial effects of NaB on colorectal cancer may be reduced by green tea phenolic supplementation. This valuable information should be of assistance in choosing a rational design for more effective diet-driven therapeutic interventions in the prevention or treatment of colorectal cancer.

Molecular mechanisms for inhibition of colon cancer cells by combined epigenetic-modulating epigallocatechin gallate and sodium butyrate

“…Two given compounds can act differently at different dose combinations. From our MTT assays we showed that at 2 mM NaB and 10 μM EGCG there was no additive or synergistic effect observed in HT-29 cells which was the same cell line chosen for the previous study [34]. Therefore, dose appears to be crucial in determining chemotherapeutic effects.…”

“…On the contrary, a study showed that EGCG interferes with butyrate-induced differentiation in colon cancer cells by preventing the cellular uptake of NaB [34]. However, in the study conducted, the dose chosen was based on the optimal values of the individual compounds and not on the combination of the compounds.…”

Ribosomal protein S15A promotes malignant transformation and predicts poor outcome in colorectal cancer through misregulation of p53 signaling pathway

“…Colorectal cancer (CRC) is one of the leading causes of death in western countries (1), and the incidence is still increasing. Approximately 70% of patients with CRC are >65 years while the disease is rare under the age of 45 (2).…”

Histone Deacetylase Inhibitory Activity of Peanut Testa Extracts against Human Cancer Cell Lines

“…Treatments with HDAC inhibitors usually resulted in growth arrest, apoptosis and inhibition of angiogenesis in cancer cells (Marks and Xu ; Sánchez‐Tena et al . ), with the cancer cell apoptosis effect being due to a shift in the balance of pro‐ and anti‐apoptotic genes (Carew et al . ).…”

“…HDAC inhibitors acting on classical HDACs have been classified into four subtypes based on their chemical structures: (1) aliphatic acids or short chain fatty acids; (2) hydroxamic acids; (3) benzamides; and (4) cyclic peptides (Hrabeta et al 2014). Treatments with HDAC inhibitors usually resulted in growth arrest, apoptosis and inhibition of angiogenesis in cancer cells (Marks and Xu 2009;Sánchez-Tena et al 2013), with the cancer cell apoptosis effect being due to a shift in the balance of pro-and anti-apoptotic genes (Carew et al 2008). Because of their low toxicity, HDAC inhibitors constitute a promising treatment for cancer, especially in combination with other chemotherapeutic agents (Carew et al 2008;Bots and Johnstone 2009;Ma et al 2009).…”