Acetate Induces Growth Arrest in Colon Cancer Cells Through Modulation of Mitochondrial Function.

Meliz Sahuri-Arisoylu,S W Annie Bligh,Jimmy D Bell,Elizabeth Louise Thomas,Noriko Shinjyo,Alistair V W Nunn,Geoffrey W Guy,Rhys R Mould

doi:10.3389/fnut.2021.588466

Meliz Sahuri-Arisoylu, S W Annie Bligh + Show 6 more

Open Access

https://doi.org/10.3389/fnut.2021.588466

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Abstract

Acetate is one of the main short chain fatty acids produced in the colon when fermentable carbohydrates are digested. It has been shown to affect normal metabolism, modulating mitochondrial function, and fatty acid oxidation. Currently, there is no clear consensus regarding the effects of acetate on tumorigenesis and cancer metabolism. Here, we investigate the metabolic effects of acetate on colon cancer. HT29 and HCT116 colon cancer cell lines were treated with acetate and its effect on mitochondrial proliferation, reactive oxygen species, density, permeability transition pore, cellular bioenergetics, gene expression of acetyl-CoA synthetase 1 (ACSS1) and 2 (ACSS2), and lipid levels were investigated. Acetate was found to reduce proliferation of both cell lines under normoxia as well as reducing glycolysis; it was also found to increase both oxygen consumption and ROS levels. Cell death observed was independent of ACSS1/2 expression. Under hypoxic conditions, reduced proliferation was maintained in the HT29 cell line but no longer observed in the HCT116 cell line. ACSS2 expression together with cellular lipid levels was increased in both cell lines under hypoxia which may partly protect cells from the anti-proliferative effects of reversed Warburg effect caused by acetate. The findings from this study suggest that effect of acetate on proliferation is a consequence of its impact on mitochondrial metabolism and during normoxia is independent of ACCS1/2 expression.

Highlights

Acetate, one of the main short chain fatty acids produced as a result of ingestion of fermentable carbohydrates has previously been shown to demonstrate anti-tumorigenic effects following its delivery as acetate encapsulated in liposomes [1]
Acetate Treatment Reduces Cell Viability and Proliferation. The viability of both HT29 and HCT116 cells was significantly reduced after 24 h treatment with 10 mM acetate (Figures 1A,B), there was no effect with 1 mM acetate treatment
In this study we report that acetate increases oxygen consumption and ROS production while reducing glycolysis and cell proliferation

Summary

Introduction

One of the main short chain fatty acids produced as a result of ingestion of fermentable carbohydrates has previously been shown to demonstrate anti-tumorigenic effects following its delivery as acetate encapsulated in liposomes [1]. There is conflicting evidence regarding its effects; acetate has been shown to reduce cell viability of colon cancer cells in vitro [2, 3] and reduce cancer cell proliferation in the liver in vivo [4]. Acetate has been shown to increase colon cancer cell death in combination with propionate; an effect further increased at a reduced pH [5]. Others have reported no effect of acetate on colon cancer cell lines, despite showing that other short chain fatty acids, butyrate and propionate, reduce cell proliferation [6,7,8,9]. The underlying mechanisms have not been fully elucidated, Jan et al suggest that acetate (and other SCFAs) induce cell death through mitochondrial changes, such as swelling and increased ROS production [3].

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