Mechanistic difference of NF-kappaB in lung physiology and tumorigenesis

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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.