Propionibacteria induce apoptosis of colorectal carcinoma cells via short-chain fatty acids acting on mitochondria

Abstract

The genus Propionibacterium is composed of dairy and cutaneous bacteria which produce short-chain fatty acids (SCFA), mainly propionate and acetate, by fermentation. Here, weshowthatP.acidipropioniciandfreudenreichii,twospecies which can survive in the human intestine, can kill two human colorectal carcinoma cell lines by apoptosis. Propionate and acetate were identified as the major cytotoxic components secreted bythebacteria. Bacterialculturesupernatantsaswell as pure SCFA induced typical signs of apoptosis including a lossofmitochondrialtransmembranepotential,thegeneration ofreactiveoxygenspecies,caspase-3processing,andnuclear chromatin condensation. The oncoprotein Bcl-2, which is known to prevent apoptosis via mitochondrial effects, and the cytomegalovirus-encoded protein vMIA, which inhibits apoptosis and interacts with the mitochondrial adenine nucleotide translocator (ANT), both inhibited cell death induced by propionibacterial SCFA, suggesting that mitochondria and ANT are involved in the cell death pathway. Accordingly, propionate and acetate induced mitochondrial swelling when added to purified mitochondria in vitro. Moreover, they specifically permeabi-lize proteoliposomes containing ANT, indicating that ANT can be a critical target in SCFA-induced apoptosis. We suggest that propionibacteria could constitute probiotics efficient in digestive cancer prophylaxis via their ability to produce apoptosis-inducing SCFA.

Influência de frações da parede celular de levedura (Saccharomyces cerevisiae) sobre os índices séricos de glicose e lipídios, microbiota intestinal e produção de ácidos graxos voláteis (AGV) de cadeias curtas de ratos em crescimento

“…influenciar algumas fases do metabolismo hepático, como a síntese de colesterol, bem como pode produzir, por apoptose, a morte de células cancerígenas no colo e no reto 27 , o ácido butírico alcança muito pouco o fígado, e é o ácido graxo menos utilizado como fonte de energia para o enterócito colônico podendo, entretanto, apresentar ação antiinflamatória, agindo sobre o sistema imunológico e antitumoral promovendo apoptose de células cancerígenas e hiperacetilação da histona H 4 e a estabilização de oncogenes 56 .…”

Short-chain fatty acids induced autophagy serves as an adaptive strategy for retarding mitochondria-mediated apoptotic cell death

“…23 In fact, the fermentation products of Propionibacterium, propionate and acetate have been identified to enhance ROS generation in human colorectal carcinoma cell lines. 24 Following propionate treatment, the percentage of cells positively stained for carboxy-DCF was increased (Figure 4f and g), which was attenuated on adding the antioxidant N-acetylcysteine (NAC). We also noticed that the cells positively stained with carboxy-DCF were those with impaired mitochondria membrane potential as reflected by reduced MitoTracker Red staining (Figure 4h).…”

Mitochondria as therapeutic targets for cancer chemotherapy

“…(Yu et al, 2000) Butyrate Chemoprevention Induces PT in isolated mitochondria and ANT proteoliposomes. (Jan et al, 2002;Heerdt et al, 2003) Carbenoxolone…”