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首页> 外文期刊>Cell cycle >FM19G11: A new modulator of hif that links mTOR activation with the DNA damage checkpoint pathways.
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FM19G11: A new modulator of hif that links mTOR activation with the DNA damage checkpoint pathways.

机译：FM19G11：一种新的hif调节剂，它将mTOR激活与DNA损伤检查点途径联系起来。

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摘要

The network consisting of mTOR and p53 pathways is crucial to understanding a wide variety of physiological and pathological events, including cancer and aging. In addition, the HIF1alpha protein, a downstream target of mTOR, is a hallmark of different tumor types and was the desired strategy of many drug discovery efforts. Here we present the novel chemical entity FM19G11, a new modulator of HIF1alpha expression, which was used as a molecular tool to dissect and further characterize the cross-talk between these signaling cascades in human colon carcinoma cell lines. To our knowledge, FM19G11 is the first drug that triggers a DNA damage response (DDR) associated with G(1)/S-phase arrest in a p53-dependent manner, due to rapid hyper-activation of the growth signaling pathway through mTOR. Assessment of colonies demonstrated that FM19G11 decreases the clonogenicity of HT29, HCT116/p53(+/+) and HCT116/p53(-/-) cells. Moreover, FM19G11 causes significant lower colony growth in soft agar of p53-proficient human colon cancer cells. Consequently, p53 sensitizes human colon cancer cells to FM19G11 by significant reduction of their viability, lessening their colony formation capability and shrinking their anchorage-independent growth. Cell signaling studies served to assign a new mode of action to FM19G11, whose tumor-suppressant activity compromises the survival of functional p53 malignant cells.
机译：由mTOR和p53途径组成的网络对于理解各种生理和病理事件（包括癌症和衰老）至关重要。另外，HIF1α蛋白是mTOR的下游靶标，是不同肿瘤类型的标志，并且是许多药物发现工作的理想策略。在这里，我们介绍了新型化学实体FM19G11，它是一种HIF1alpha表达的新型调节剂，它被用作分子工具来解剖并进一步表征人类结肠癌细胞系中这些信号传导级联之间的串扰。据我们所知，FM19G11是第一种以依赖p53的方式触发与G（1）/ S期停滞有关的DNA损伤反应（DDR）的药物，这是由于生长信号通路通过mTOR的快速过度激活所致。菌落的评估表明，FM19G11降低了HT29，HCT116 / p53（+ / +）和HCT116 / p53（-/-）细胞的克隆性。此外，FM19G11会导致p53阳性的人结肠癌细胞在软琼脂中的集落明显降低。因此，p53通过显着降低其生存能力，降低其集落形成能力并缩小其与锚定无关的生长，使人结肠癌细胞对FM19G11敏感。细胞信号研究为FM19G11赋予了新的作用方式，FM19G11的肿瘤抑制活性损害了功能性p53恶性细胞的存活。

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