摘要
Cancer cells exhibit unique metabolic features and take advantage of them to enhance their survival and proliferation. While the activation of NRF2 (nuclear factor erythroid 2-like 2; NFE2L2), a CNC (cap‘n’collar) family transcription factor, is effective for the prevention and alleviation of various diseases, NRF2 contributes to cancer malignancy by promoting aggressive tumorigenesis and conferring therapeutic resistance. NRF2-mediated metabolic reprogramming and increased antioxidant capacity underlie the malignant behaviors of NRF2-activated cancer cells. Another member of the CNC family, NRF1, plays a key role in the therapeutic resistance of cancers. Since NRF1 maintains proteasome activity by inducing proteasome subunit genes in response to proteasome inhibitors, NRF1 protects cancer cells from proteotoxicity induced by anticancer proteasome inhibitors. An important metabolite that activates NRF1 is UDP-GlcNAc (uridine diphosphate N-acetylglucosamine), which is abundantly generated in many cancer cells from glucose and glutamine via the hexosamine pathway. Thus, the metabolic signatures of cancer cells are closely related to the oncogenic and tumor-promoting functions of CNC family members. In this review, we provide a brief overview of NRF2-mediated cancer malignancy and elaborate on NRF1-mediated drug resistance affected by an oncometabolite UDP-GlcNAc.
摘要译文
癌细胞表现出独特的代谢特征，并利用它们来增强其存活和增殖。虽然NRF2的激活（核因子红斑2状2; NFE2L2），一种CNC（Cap'N'collar）家族转录因子，对防治各种疾病有效，NRF2通过促进激进的肿瘤鉴定和赋予治疗性抗性而导致癌症恶性肿瘤。 NRF2介导的代谢重编程和增加的抗氧化能力利于NRF2活性癌细胞的恶性行为。 NRF1的CNC系列的另一个成员在癌症的治疗抵抗力中起着关键作用。由于NRF1通过响应蛋白酶体抑制剂诱导蛋白酶体亚基基因而维持蛋白酶体活性，因此NRF1保护来自抗癌蛋白酶体抑制剂诱导的蛋白毒性的癌细胞。激活NRF1的重要代谢物是UDP-GLCNAc（尿苷二磷酸n-乙酰葡糖胺），其在许多来自葡萄糖和谷氨酰胺的许多癌细胞中大量产生的通过六甲胺途径。因此，癌细胞的代谢特征与CNC家族成员的致癌和肿瘤促进功能密切相关。在本综述中，我们简要概述了NRF2介导的癌症恶性肿瘤，并详细阐述了受卵巢替代素UDP-GLCNAc影响的NRF1介导的耐药性。
Hiroki Sekine[ [*];Hozumi Motohashi. Roles of CNC Transcription Factors NRF1 and NRF2 in Cancer[J]. Cancers, 2021,13(3): 541