Abstract
In order to exploit the rich reservoir of marine cold-adapted bacteria as a source of bioactive metabolites, ethyl acetate crude extracts of thirteen polar marine bacteria were tested for their antiproliferative activity on A549 lung epithelial cancer cells. The crude extract from Pseudoalteromonas haloplanktis TAC125 was the most active in inhibiting cell proliferation. Extensive bioassay-guided purification and mass spectrometric characterization allowed the identification of 4-hydroxybenzoic acid (4-HBA) as the molecule responsible for this bioactivity. We further demonstrate that 4-HBA inhibits A549 cancer cell proliferation with an IC50 value ≤ 1 μg ml−1, and that the effect is specific, since the other two HBA isomers (i.e. 2-HBA and 3-HBA) were unable to inhibit cell proliferation. The effect of 4-HBA is also selective since treatment of normal lung epithelial cells (WI-38) with 4-HBA did not affect cell viability. Finally, we show that 4-HBA is able to activate, at the gene and protein levels, a specific cell death signaling pathway named pyroptosis. Accordingly, the treatment of A549 cells with 4-HBA induces the transcription of (amongst others) caspase-1, IL1β, and IL18 encoding genes. Studies needed for the elucidation of mode of action of 4-HBA will be instrumental in depicting novel details of pyroptosis.
Highlights
Lung cancer is an extremely important health concern that affects millions of people worldwide[1,2], and any progress leading to improvement of cancer survival rates is a global priority
A549 tumor cells were treated with different concentrations (1, 10 and 100 μg ml−1) of the total extracts for 24 hours and 48 hours, and compared with cells treated with the negative control extract
We evaluated the antiproliferative activity on tumor cells of ethyl acetate crude extracts of cold-adapted bacteria belonging to the genera Pseudoalteromonas, Pseudomonas, Psychrobacter and Psychromonas
Summary
Lung cancer is an extremely important health concern that affects millions of people worldwide[1,2], and any progress leading to improvement of cancer survival rates is a global priority. Traditional cancer chemotherapy has mainly been based on the use of highly cytotoxic drugs that non- target all dividing cells and may only result in a modest improvement in patients that become immunosuppressed as chemotherapeutics kill all proliferating cells including monocytes and lymphocytes. For this reason, a new trend in anticancer research has arisen focusing on the discovery of new natural drugs that induce specific programmed cell death mediated by immunogenic signals. This bacterium produces 4-hydroxybenzoic acid that activates pyroptosis in A549 cells without affecting viability in normal cells
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