Acetate-induced apoptosis in colorectal carcinoma cells involves lysosomal membrane permeabilization and cathepsin D release

Abstract

Colorectal carcinoma (CRC) is one of the most common causes of cancer-related mortality. Short-chain fatty acids secreted by dietary propionibacteria from the intestine, such as acetate, induce apoptosis in CRC cells and may therefore be relevant in CRC prevention and therapy. We previously reported that acetic acid-induced apoptosis in Saccharomyces cerevisiae cells involves partial vacuole permeabilization and release of Pep4p, the yeast cathepsin D (CatD), which has a protective role in this process. In cancer cells, lysosomes have emerged as key players in apoptosis through selective lysosomal membrane permeabilization (LMP) and release of cathepsins. However, the role of CatD in CRC survival is controversial and has not been assessed in response to acetate. We aimed to ascertain whether LMP and CatD are involved in acetate-induced apoptosis in CRC cells. We showed that acetate per se inhibits proliferation and induces apoptosis. More importantly, we uncovered that acetate triggers LMP and CatD release to the cytosol. Pepstatin A (a CatD inhibitor) but not E64d (a cathepsin B and L inhibitor) increased acetate-induced apoptosis of CRC cells, suggesting that CatD has a protective role in this process. Our data indicate that acetate induces LMP and subsequent release of CatD in CRC cells undergoing apoptosis, and suggest exploiting novel strategies using acetate as a prevention/therapeutic agent in CRC, through simultaneous treatment with CatD inhibitors.

Apoptotic effect of sodium acetate on a human gastric adenocarcinoma epithelial cell line

“…It has been established that acetate induces mitochondrial apoptotic death, as well as MP in RCs. Caspase-3 plays a crucial role in the cell death process (Jan et al, 2002;Marques et al, 2013;Oliveira et al, 2015). In this study, caspase-8 activity changed weakly after 6 h, while caspase-9 activity increased by 11% after 6 h in the presence of 50 mM sodium acetate.…”

“…Sodium acetate has been reported to induce differentiation as well as apoptosis, and arrest growth in colorectal cancer cell lines. The antitumor effect of acetate stems from its ability to induce cell death in colon cancer cells via mitochondria-mediated apoptosis or necrosis (Marques et al, 2013). Our previous study has also shown that 12.5 mM sodium acetate stimulates AGS cell viability and proliferation in a dose-dependent manner.…”

“…Acetate inhibits human neutrophil migration toward C5a or formyl-methionyl-leucyl-phenylalanine (fMLP) in a GPR43-dependent manner under inflammatory conditions (Vinolo et al, 2011). Acetate also induces partial lysosomal membrane permeabilization and the subsequent release of cathepsin D to the cytosol of apoptotic colorectal cancer cells (Marques et al, 2013).…”

Lipoic acid induces p53-independent cell death in colorectal cancer cells and potentiates the cytotoxicity of 5-fluorouracil

“…Derived from octanoic acid, LA shares structural homology with short fatty acids such as butyrate and propionate, which are known to induce apoptosis in CRC cells in the millimolar range (Marques et al 2013;Ruemmele et al 2003). We showed that already lower concentrations of LA (250-500 µM) are sufficient to efficiently trigger cell death in different CRC cell lines.…”

Honokiol exhibits enhanced antitumor effects with chloroquine by inducing cell death and inhibiting autophagy in human non-small cell lung cancer cells

“…Cathepsin D, a member of the lysosomal aspartyl cathepsin family, plays a crucial role in cell fate and tissue homeostasis through apoptosis (21). Based on the above results, HNK induced apoptosis, thus we investigated the effect of HNK on cathepsin D expression.…”