Mechanistic difference of NF-kappaB in lung physiology and tumorigenesis

摘要 转录因子NF-κB对肿瘤的发生和治疗耐药至关重要，但我们有 由于它在生理学和生理学上的作用同样重要，因此无法成功地将其用于临床治疗 尤其是东道主防守。梳理NF-κB的这些功能将克服这一障碍，导致 抗击癌症的有力手段。虽然驱动NF-κB激活的核心机制已经被很好地定义和 在大多数生理和致癌条件下，生理和致癌机制的差异是相同的。 致癌的NF-κB仍然是一个难题。最近，我们第一次证明了外在的/ 炎症和内源性/致癌信号诱导不同激活模式和不同形式的NF-κB 正常肺细胞和肺癌细胞。此外，我们还首次确定了PDZ-LIM 含有结构域的蛋白PDLIM2选择性地抑制“致癌”而不是“生理”激活 并可作为肺癌小鼠模型的单一或联合治疗的靶点。基于 在这个提案中，我们将确定PDLIM2的作用分子机制 作为核因子-κB功能的决定因素。我们还将剖析这一调控的作用和分子机制。 NF-κB的“致癌”和“生理性”激活在肺肿瘤发生和生理宿主防御中的作用 抗肺部感染。这些研究意义重大，因为我们知道核因子-κB是一种强大的肿瘤促进剂 与几乎所有人类癌症有关，但由于其生理重要性，目前不能在临床上作为靶点。此外，这些研究在核因子-κB与癌症方面都有概念和技术上的创新， 由于它们开辟了研究核因子-κB在癌症和生理中的差异调节和作用的新途径， 并可能导致新的临床可行的方法，选择性地靶向致病的NF-κB用于癌症治疗。

Abstract The transcription factor NF-κB is critically important for tumorigenesis and therapeutic resistance but we have been unable to successfully target it for clinical treatment due to its equally important roles in physiology and host defense in particular. Teasing apart these functions of NF-κB will overcome this barrier resulting in a powerful means to fight cancer. While the core mechanism driving NF-κB activation has been well defined and is the same under most physiological and oncogenic conditions, the mechanistic difference in physiological vs. oncogenic NF-κB still remains a conundrum. Recently, we have demonstrated, for the first time, that extrinsic/ inflammatory and intrinsic/oncogenic signals induce different activation patterns and different forms of NF-κB in normal lung cells and lung cancer cells. Moreover, we have identified, also for the first time, the PDZ-LIM domain-containing protein PDLIM2 that selectively suppresses the ‘oncogenic’ but not ‘physiologic’ activation of NF-κB and can be targeted as mono- or combination therapy in murine models of lung cancer. Based on these novel discoveries, in this proposal we will determine the molecular mechanisms by which PDLIM2 acts as a determinant of NF-κB function. We will also dissect the roles and molecular mechanisms of this regulation of the ‘oncogenic’ and ‘physiologic’ activation of NF-κB in lung tumorigenesis and physiological host defense against pulmonary infection. These studies are significant, because we know NF-κB is a strong tumor promoter linked to almost all human cancers but cannot currently be targeted in the clinic given its physiological importance. Also, these studies have both conceptual and technical innovations regarding NF-κB and cancer, since they open new avenues to study the differential regulation and action of NF-κB in cancer and physiology, and may lead to new clinically feasible approaches to selectively target pathogenic NF-κB for cancer therapy.