Jones Trace M, Carew Jennifer S, Bauman Julie E, Nawrocki Steffan T
Department of Medicine, The University of Arizona Cancer Center, Tucson, AZ 85724, USA.
Cancers (Basel). 2021 Jun 29;13(13):3250. doi: 10.3390/cancers13133250.
Head and neck cancer is diagnosed in nearly 900,000 new patients worldwide each year. Despite this alarming number, patient outcomes, particularly for those diagnosed with late-stage and human papillomavirus (HPV)-negative disease, have only marginally improved in the last three decades. New therapeutics that target novel pathways are desperately needed. NEDDylation is a key cellular process by which NEDD8 proteins are conjugated to substrate proteins in order to modulate their function. NEDDylation is closely tied to appropriate protein degradation, particularly proteins involved in cell cycle regulation, DNA damage repair, and cellular stress response. Components of the NEDDylation pathway are frequently overexpressed or hyperactivated in many cancer types including head and neck cancer, which contribute to disease progression and drug resistance. Therefore, targeting NEDDylation could have a major impact for malignancies with alterations in the pathway, and this has already been demonstrated in preclinical studies and clinical trials. Here, we will survey the mechanisms by which aberrant NEDDylation contributes to disease pathogenesis and discuss the potential clinical implications of inhibiting NEDDylation as a novel approach for the treatment of head and neck cancer.
全球每年有近90万新患者被诊断出患有头颈癌。尽管这一数字令人震惊，但在过去三十年中，患者的治疗结果，尤其是那些被诊断为晚期和人乳头瘤病毒（HPV）阴性疾病的患者，仅略有改善。迫切需要针对新途径的新疗法。NEDDylation是一个关键的细胞过程，通过该过程，NEDD8蛋白与底物蛋白结合以调节其功能。NEDDylation与适当的蛋白质降解密切相关，特别是与细胞周期调节、DNA损伤修复和细胞应激反应相关的蛋白质。NEDDylation途径的成分在包括头颈癌在内的许多癌症类型中经常过度表达或过度激活，这有助于疾病进展和耐药性。因此，靶向NEDDylation可能对该途径发生改变的恶性肿瘤产生重大影响，这已经在临床前研究和临床试验中得到证实。在这里，我们将探讨异常NEDDylation导致疾病发病机制的机制，并讨论抑制NEDDylation作为治疗头颈癌的新方法的潜在临床意义。
