细菌代谢物引发的信号变化,在与乳腺癌相关的致癌病中,在促进疾病进展中发挥作用。我们证明硫酸吲哚酚(IS),色氨酸代谢产物,在乳腺癌模型中具有细胞抑制特性。是补充,在对应于人类血清参考范围的浓度中,在小鼠乳腺癌模型中抑制肿瘤向周围组织的浸润和转移形成。在细胞模型中,IS抑制NRF2和诱导iNOS,导致氧化和亚硝化应激的诱导,and,因此,减少细胞增殖;增强的氧化和亚硝化应激在随后的细胞停滞中至关重要。IS还抑制了上皮-间质转化,对抑制细胞运动和排骨至关重要。此外,呈现细胞低代谢,导致醛脱氢酶阳性细胞减少。使用CH223191对孕烷X受体和使用酮康唑对芳基烃受体的药理学抑制减少了IS引起的作用,表明这些受体是这些模型中IS的主要受体。最后,我们发现,在乳腺癌中,形成IS的人类酶(Cyp2E1,Sult1A1和Sult1A2)的表达增加与更好的生存率相关。在三重阴性情况下失去的效果。一起来看,IS,类似于吲哚丙酸(另一种色氨酸代谢产物),具有细胞抑制特性,并且负责IS形成的代谢机制的较高表达支持乳腺癌的生存。
Changes to bacterial metabolite-elicited signaling, in oncobiosis associated with breast cancer, plays a role in facilitating the progression of the disease. We show that indoxyl-sulfate (IS), a tryptophan metabolite, has cytostatic properties in models of breast cancer. IS supplementation, in concentrations corresponding to the human serum reference range, suppressed tumor infiltration to the surrounding tissues and metastasis formation in a murine model of breast cancer. In cellular models, IS suppressed NRF2 and induced iNOS, leading to induction of oxidative and nitrosative stress, and, consequently, reduction of cell proliferation; enhanced oxidative and nitrosative stress are crucial in the subsequent cytostasis. IS also suppressed epithelial-to-mesenchymal transition vital for suppressing cellular movement and diapedesis. Furthermore, IS rendered cells hypometabolic, leading to a reduction in aldehyde-dehydrogenase positive cells. Pharmacological inhibition of the pregnane-X receptor using CH223191 and the aryl-hydrocarbon receptor using ketoconazole diminished the IS-elicited effects, suggesting that these receptors were the major receptors of IS in these models. Finally, we showed that increased expression of the human enzymes that form IS (Cyp2E1, Sult1A1, and Sult1A2) is associated with better survival in breast cancer, an effect that is lost in triple negative cases. Taken together, IS, similar to indolepropionic acid (another tryptophan metabolite), has cytostatic properties and higher expression of the metabolic machinery responsible for the formation of IS supports survival in breast cancer.