We recently described a positive feedback loop connecting c-MYC, NAMPT, DBC1 and SIRT1 that contributes to unrestricted cancer cell proliferation. Here we determine the relevance of the loop for serrated route intestinal tumorigenesis using genetically well-defined BrafV600E and K-rasG12D mouse models. In both models we show that c-MYC and SIRT1 protein expression increased through progression from hyperplasia to invasive carcinomas and metastases. It correlated with high NAMPT expression and was directly associated to activation of the oncogenic drivers. Assessing functional and molecular consequences of pharmacological interference with factors of the loop, we found that inhibition of NAMPT resulted in apoptosis and reduced clonogenic growth in human BRAF-mutant colorectal cancer cell lines and patient-derived tumoroids. Blocking SIRT1 activity was only effective when combined with a PI3K inhibitor, whereas the latter antagonized the effects of NAMPT inhibition. Interfering with the positive feedback loop was associated with down-regulation of c-MYC and temporary de-repression of TP53, explaining the anti-proliferative and pro-apoptotic effects. In conclusion we show that the c-MYC-NAMPT-DBC1-SIRT1 positive feedback loop contributes to murine serrated tumor progression. Targeting the feedback loop exerted a unique, dual therapeutic effect of oncoprotein inhibition and tumor suppressor activation. It may therefore represent a promissing target for serrated colorectal cancer, and presumably for other cancer types with deregulated c-MYC.

中文翻译：

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通过干扰NAMPT和SIRT1及其与小鼠锯齿状肠肿瘤发生中的致癌驱动因子的关联来靶向c-MYC。

我们最近描述了一个连接c-MYC，NAMPT，DBC1和SIRT1的正反馈回路，该回路有助于不受限制的癌细胞增殖。在这里，我们使用遗传学上定义明确的BrafV600E和K-rasG12D小鼠模型，确定锯齿状路径肠肿瘤发生过程中环的相关性。在这两个模型中，我们显示c-MYC和SIRT1蛋白表达通过从增生到浸润性癌和转移的过程而增加。它与NAMPT高表达相关，并且与致癌驱动因子的激活直接相关。评估药理学干扰环路因素的功能和分子后果，我们发现抑制NAMPT会导致人BRAF突变结肠直肠癌细胞系和患者来源的类瘤细胞凋亡并降低克隆形成性生长。仅当与PI3K抑制剂联用时，阻断SIRT1的活性才有效，而后者则拮抗NAMPT的抑制作用。干扰正反馈回路与c-MYC的下调和TP53的暂时抑制有关，解释了抗增殖和促凋亡作用。总之，我们表明c-MYC-NAMPT-DBC1-SIRT1阳性反馈回路有助于鼠锯齿状肿瘤的进展。靶向反馈回路发挥了癌蛋白抑制和肿瘤抑制因子激活的独特双重治疗作用。因此，它可能是锯齿状结直肠癌的可能靶标，大概是c-MYC失调的其他癌症类型的靶标。干扰正反馈回路与c-MYC的下调和TP53的暂时抑制有关，解释了抗增殖和促凋亡作用。总之，我们表明c-MYC-NAMPT-DBC1-SIRT1阳性反馈回路有助于鼠锯齿状肿瘤的进展。靶向反馈回路发挥了癌蛋白抑制和肿瘤抑制因子激活的独特双重治疗作用。因此，它可能是锯齿状结直肠癌的可能靶标，大概是c-MYC失调的其他癌症类型的靶标。干扰正反馈回路与c-MYC的下调和TP53的暂时抑制有关，解释了抗增殖和促凋亡作用。总之，我们表明c-MYC-NAMPT-DBC1-SIRT1阳性反馈回路有助于鼠锯齿状肿瘤的进展。靶向反馈回路发挥了癌蛋白抑制和肿瘤抑制因子激活的独特双重治疗作用。因此，它可能是锯齿状结直肠癌的可能靶标，大概是c-MYC失调的其他癌症类型的靶标。总之，我们表明c-MYC-NAMPT-DBC1-SIRT1阳性反馈回路有助于鼠锯齿状肿瘤的进展。靶向反馈回路发挥了癌蛋白抑制和肿瘤抑制因子激活的独特双重治疗作用。因此，它可能是锯齿状结直肠癌的可能靶标，大概是c-MYC失调的其他癌症类型的靶标。总之，我们表明c-MYC-NAMPT-DBC1-SIRT1阳性反馈回路有助于鼠锯齿状肿瘤的进展。靶向反馈回路发挥了癌蛋白抑制和肿瘤抑制因子激活的独特双重治疗作用。因此，它可能是锯齿状结直肠癌的可能靶标，大概是c-MYC失调的其他癌症类型的靶标。