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Propolis augments apoptosis induced by butyrate via targeting cell survival pathways.

ABSTRACT: Diet is one of the major lifestyle factors affecting incidence of colorectal cancer (CC), and despite accumulating evidence that numerous diet-derived compounds modulate CC incidence, definitive dietary recommendations are not available. We propose a strategy that could facilitate the design of dietary supplements with CC-preventive properties. Thus, nutrient combinations that are a source of apoptosis-inducers and inhibitors of compensatory cell proliferation pathways (e.g., AKT signaling) may produce high levels of programmed death in CC cells. Here we report the combined effect of butyrate, an apoptosis inducer that is produced through fermentation of fiber in the colon, and propolis, a honeybee product, on CC cells. We established that propolis increases the apoptosis of CC cells exposed to butyrate through suppression of cell survival pathways such as the AKT signaling. The programmed death of CC cells by combined exposure to butyrate and propolis is further augmented by inhibition of the JNK signaling pathway. Analyses on the contribution of the downstream targets of JNK signaling, c-JUN and JAK/STAT, to the apoptosis of butyrate/propolis-treated CC cells ascertained that JAK/STAT signaling has an anti-apoptotic role; whereas, the role of cJUN might be dependent upon regulatory cell factors. Thus, our studies ascertained that propolis augments apoptosis of butyrate-sensitive CC cells and re-sensitizes butyrate-resistant CC cells to apoptosis by suppressing AKT signaling and downregulating the JAK/STAT pathway. Future in vivo studies should evaluate the CC-preventive potential of a dietary supplement that produces high levels of colonic butyrate, propolis, and diet-derived JAK/STAT inhibitors.

SUBMITTER: Drago E

PROVIDER: S-EPMC3762847 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Propolis augments apoptosis induced by butyrate via targeting cell survival pathways.

Drago Eric E Bordonaro Michael M Lee Seon S Atamna Wafa W Lazarova Darina L DL

PloS one 20130904 9

Diet is one of the major lifestyle factors affecting incidence of colorectal cancer (CC), and despite accumulating evidence that numerous diet-derived compounds modulate CC incidence, definitive dietary recommendations are not available. We propose a strategy that could facilitate the design of dietary supplements with CC-preventive properties. Thus, nutrient combinations that are a source of apoptosis-inducers and inhibitors of compensatory cell proliferation pathways (e.g., AKT signaling) may ...[more]

PMID: 24023824

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Project description:The effects and underlying mechanisms of butyrate and butyrate+niacin on apoptosis in sheep rumen epithelial cells were investigated. Cells were exposed to butyrate (0-140 mM) for 6 h. A low concentration (20 mM) of butyrate increased cell viability and promoted growth whereas high concentrations (40-140 mM) inhibited proliferation. Cells were then cocultured with 120 mM butyrate and niacin (0-100 mM) for 6 h. Niacin addition attenuated butyrate-induced cellular damage and promoted proliferation at 20-80 mM; 40 mM presented the optimal effect. Higher concentrations (100 mM) of niacin resulted in low cell viability. Subsequent experiments confirmed that 120 mM butyrate increased intracellular reactive oxygen species (ROS) production and reduced the intracellular total antioxidant capacity (T-AOC) versus the untreated control. Compared with 120 mM butyrate, cotreatment with 40 mM niacin significantly reduced the intracellular ROS content and increased the intracellular T-AOC. Flow cytometry analysis revealed that 120 mM butyrate increased the proportion of apoptotic cells by 17.8% versus the untreated control, and 120 mM butyrate+40 mM niacin treatment reduced the proportion of apoptotic cells by 28.6% and 39.4% versus the untreated control and butyrate treatment, respectively. Treatment with 120 mM butyrate increased caspase-9 and p53 mRNA levels and decreased the expression of Bcl-2 and Bax, and the Bcl-2/Bax ratio versus the untreated control. Treatment with 120 mM butyrate+40 mM niacin downregulated the expression of caspase-3 and p53 and increased the expression of Bcl-2 and Bax versus butyrate treatment alone but had no effect on the Bcl-2/Bax ratio. Thus, high concentrations of butyrate may induce rumen epithelial cell apoptosis by increasing oxidative stress and inducing caspase-9 and p53 expression. Cotreatment with niacin regulates apoptosis-related gene expression by reducing intracellular ROS production and DNA damage and downregulating caspase-3 and p53 expressions to protect rumen epithelial cells against butyrate-induced apoptosis.

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Propolis augments apoptosis induced by butyrate via targeting cell survival pathways.

Publications

Propolis augments apoptosis induced by butyrate via targeting cell survival pathways.

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