Molecular mechanisms of cNOS-mediated NF-kappa B activation in regulation of ultraviolet B light-induced photocarcinogenic responses

摘要 紫外线B辐射（UVB）是一种环境致癌物，是引起皮肤病的主要因素之一。 皮肤癌形成。NF-kB的激活已被证明在癌发生中起重要作用， 抑制细胞凋亡并因此增强细胞转化。因此，NF-kB信令网络已经被 是开发用于预防UVB诱导的皮肤癌发生的治疗剂的主要靶点。我们 报道了一种由组成型一氧化氮合酶介导的NF-κ B活化的非经典途径 UVB照射后早期（6 h），cNOS表达明显下降。与此同时，cNOS的激活有望 通过一氧化氮（NO·）和超氧化物（O2−·）产生有毒的过氧亚硝酸盐（ONOO−）来促进细胞损伤。 因此，UVB诱导的cNOS激活通过增加DNA损伤的程度促进皮肤癌的发生。 损伤，降低DNA损伤修复能力，促进受损细胞存活。这 这一发现表明，cNOS抑制剂可以通过阻断皮肤癌的发生， DNA损伤和NF-κ B抗凋亡活性的协同作用。cNOS作为一种生物相容性材料的一种理想性质是， 靶点是它只影响UVB诱导的而不影响TNF α诱导的NF-κ B活化。的目的 本研究旨在阐明UVB诱导皮肤致癌反应的基本分子机制 通过对cNOS协调的促死亡氧化/亚硝化应激和DNA损伤的详细研究， 作为促存活NF-κ B活化和自噬诱导。本提案的创新之处在于 UVB诱导的早期NF-kB激活仅依赖于cNOS激活的新假说; cNOS是UVB诱导的皮肤癌化学预防的潜在靶点。这 这一假说是基于cNOS在引起DNA损伤、激活NF-kB和 通过NF-κ B调节的IKKa稳定诱导自噬。此外，拟议的 调节和NF-kB-IKKa信号级联的功能作用是一种新的概念性的“逆转”， 正常IKKa-NF-kB信号传导。cNOS抑制剂在防止UVB诱导的DNA中的治疗用途 损伤，细胞死亡，以及皮肤癌发生是临床创新。这项研究可能会 从而开发用于UVB诱导的皮肤癌的化学预防和治疗的新疗法。

Abstract Ultraviolet B radiation (UVB) is an environmental carcinogen, which is one of the major causative factors of skin cancer formation. Activation of NF-kB has been shown to play an important role in carcinogenesis by inhibiting apoptosis and therefore enhancing cell transformation. Thus, the NF-kB signaling network has been a major target for development of therapeutics for prevention of UVB-induced skin carcinogenesis. We reported a non-canonical pathway for activation of NF-kB that is mediated by constitutive nitric oxide synthase (cNOS) in the early phase (6 h) after UVB irradiation. At the same time, activation of cNOS is expected to promote cell damage by producing toxic peroxynitrite (ONOO−) from nitric oxide (NO•) and superoxide (O2−•). Therefore, UVB-induced activation of cNOS promotes skin carcinogenesis by increasing the extent of DNA damage, decreasing the capacity of DNA damage repair and promoting the survival of damaged cells. This finding suggests that cNOS inhibitors could protect against development of skin cancer via blocking the synergistic effect of DNA damage and anti-apoptotic activity of NF-kB. A desirable property of cNOS as a target is that it only affects UVB-induced but not TNFa-induced NF-kB activation. The objective of this proposal is to elucidate the fundamental molecular mechanism of UVB-induced skin carcinogenic responses through a detailed study of cNOS-coordinated pro-death oxidative/nitrosative stress and DNA damage as well as pro-survival NF-kB activation and autophagy induction. The innovation of this proposal resides on the novel hypotheses that UVB-induced early phase NF-kB activation is solely dependent on cNOS activation; and cNOS is a promising potential target for chemoprevention of UVB-induced skin carcinogenesis. This hypothesis is based on the oncogenic properties of cNOS in causing DNA damage, activating NF-kB, and inducing autophagy via NF-kB-regulated stabilization of IKKa. In addition, the proposed mechanism for regulation and the functional role of NF-kB-IKKa signaling cascade is a novel conceptual ‘reversal’ of the normal IKKa-NF-kB signaling. The therapeutic use of cNOS inhibitors in preventing UVB-induced DNA damage, cell death, as well as skin carcinogenesis is clinically innovative. The proposed study can potentially lead to the development of new therapeutics for chemoprevention and treatment of UVB-induced skin cancer.