Mechanistic difference of NF-kappaB in lung physiology and tumorigenesis

摘要 转录因子NF-κB在肿瘤发生和治疗耐药性中至关重要，但我们发现， 由于其在生理学和免疫学中同样重要的作用， 特别是防御。将NF-κB的这些功能分开将克服这一障碍，从而导致 强大的手段来对抗癌症。虽然驱动NF-κB活化的核心机制已经被很好地定义， 在大多数生理和致癌条件下是相同的，生理与致癌条件下的机制差异。 致癌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/致癌信号诱导不同活化模式和不同形式的NF-κB， 正常肺细胞和肺癌细胞。此外，我们还首次确定了PDZ-LIM 一种选择性抑制“致癌”而非“生理”激活的含结构域蛋白质PDLIM 2 NF-κB的表达，并且可以在肺癌的鼠模型中作为单一或组合疗法靶向。基于 这些新的发现，在这项建议中，我们将确定PDLIM 2的分子机制， 作为NF-κB功能的决定因素。我们还将剖析这种调节的作用和分子机制 NF-κB的“致癌”和“生理”激活在肺肿瘤发生和生理宿主防御中的作用 对抗肺部感染这些研究是有意义的，因为我们知道NF-κB是一种强的肿瘤促进剂 与几乎所有人类癌症有关，但鉴于其生理重要性，目前无法在临床上靶向。此外，这些研究在NF-κB和癌症方面具有概念和技术创新， 由于它们为研究NF-κB在癌症和生理学中的差异调节和作用开辟了新的途径， 并可能导致新的临床可行的方法来选择性靶向致病性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.