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，是引起人类健康的主要致癌因素之一。 皮肤癌的形成。核因子-kB的激活已被证明在癌症的发生中发挥重要作用 抑制细胞凋亡，从而促进细胞转化。因此，核因子-kB信令网络已经 为预防UVB诱发的皮肤癌而开发的治疗药物的主要靶点。我们 报道了一种由结构型一氧化氮合酶介导的非典型的核因子-kB激活途径 (CNOS)在UVB照射后的早期(6h)。与此同时，CNOS的激活预计将 通过从一氧化氮(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的激活通过增加DNA的程度来促进皮肤癌变 损伤，降低DNA损伤修复能力，促进受损细胞存活。这 研究结果表明，cNOS抑制剂可以通过阻止皮肤癌的发生而预防皮肤癌的发生 核因子-kB对DNA损伤和抗凋亡活性的协同作用。CNOS作为一种 靶点是它只影响UVB诱导的NF-kB激活，而不影响TNFa诱导的NF-kB激活。这样做的目的是 建议阐明中波紫外线诱发皮肤致癌反应的基本分子机制 通过详细研究cNOS协调的致死、氧化/亚硝化应激和DNA损伤 作为促进生存的核因子-kB的激活和自噬诱导。这一建议的创新之处在于 新的假设认为，UVB诱导的早期核因子-kB的激活完全依赖于cNOS的激活； CNOS是UVB诱导的皮肤癌的化学预防的潜在靶点。这 假设是基于cNOS在导致DNA损伤、激活核因子-kB和 通过核因子-kB调节的Ikka的稳定来诱导自噬。此外，拟议的机制 核因子-kB-Ikka信号级联的调节和功能作用是对 正常的IKKA-NF-kB信号。一氧化氮合酶抑制剂在预防UVB诱导DNA损伤中的应用 损伤、细胞死亡以及皮肤癌变在临床上都是创新的。拟议中的研究可能会 导致化学预防和治疗UVB诱发皮肤癌的新疗法的发展。

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.