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.

中文翻译：

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假浮游假单胞菌TAC125产生4-羟基苯甲酸，诱导人A459肺腺癌细胞的凋亡。

为了利用丰富的海洋冷适应细菌库作为生物活性代谢物的来源，测试了13种极性海洋细菌的乙酸乙酯粗提物对A549肺上皮癌细胞的抗增殖活性。嗜盐假单胞菌TAC125的粗提物在抑制细胞增殖中最活跃。广泛的生物测定指导的纯化和质谱表征允许鉴定4-羟基苯甲酸（4-HBA）作为负责这种生物活性的分子。我们进一步证明4-HBA以IC ₅₀值≤1μgml ^-1抑制A549癌细胞的增殖并且该效果是特异性的，因为其他两种HBA异构体（即2-HBA和3-HBA）无法抑制细胞增殖。4-HBA的作用也是选择性的，因为用4-HBA处理正常的肺上皮细胞（WI-38）不会影响细胞活力。最后，我们证明了4-HBA能够在基因和蛋白质水平上激活一种称为“细胞凋亡”的特定细胞死亡信号转导途径。因此，用4-HBA处理A549细胞诱导了caspase-1，IL1β和IL18编码基因的转录。阐明4-HBA的作用方式所需的研究将有助于描述焦磷酸化的新细节。