Beeraka Narasimha M, Bovilla Venugopal R, Doreswamy Shalini H, Puttalingaiah Sujatha, Srinivasan Asha, Madhunapantula SubbaRao V
Center of Excellence in Molecular Biology and Regenerative Medicine (CEMR), Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka 570015, India.
Public Health Research Institute of India (PHRII), Mysuru, Karnataka 570020, India.
Cancers (Basel). 2021 Jan 14;13(2):281. doi: 10.3390/cancers13020281.
Glycated stress is mediated by the advanced glycation end products (AGE) and the binding of AGEs to the receptors for advanced glycation end products (RAGEs) in cancer cells. RAGEs are involved in mediating tumorigenesis of multiple cancers through the modulation of several downstream signaling cascades. Glycated stress modulates various signaling pathways that include p38 mitogen-activated protein kinase (p38 MAPK), nuclear factor kappa-B (NF-κB), tumor necrosis factor (TNF)-α, etc., which further foster the uncontrolled proliferation, growth, metastasis, angiogenesis, drug resistance, and evasion of apoptosis in several cancers. In this review, a balanced overview on the role of glycation and deglycation in modulating several signaling cascades that are involved in the progression of cancers was discussed. Further, we have highlighted the functional role of deglycating enzyme fructosamine-3-kinase (FN3K) on Nrf2-driven cancers. The activity of FN3K is attributed to its ability to deglycate Nrf2, a master regulator of oxidative stress in cells. FN3K is a unique protein that mediates deglycation by phosphorylating basic amino acids lysine and arginine in various proteins such as Nrf2. Deglycated Nrf2 is stable and binds to small musculoaponeurotic fibrosarcoma (sMAF) proteins, thereby activating cellular antioxidant mechanisms to protect cells from oxidative stress. This cellular protection offered by Nrf2 activation, in one way, prevents the transformation of a normal cell into a cancer cell; however, in the other way, it helps a cancer cell not only to survive under hypoxic conditions but also, to stay protected from various chemo- and radio-therapeutic treatments. Therefore, the activation of Nrf2 is similar to a double-edged sword and, if not controlled properly, can lead to the development of many solid tumors. Hence, there is a need to develop novel small molecule modulators/phytochemicals that can regulate FN3K activity, thereby maintaining Nrf2 in a controlled activation state.
糖基化应激由晚期糖基化终产物（AGE）介导，且AGEs与癌细胞中的晚期糖基化终产物受体（RAGEs）结合。RAGEs通过调节多个下游信号级联反应参与介导多种癌症的肿瘤发生。糖基化应激调节多种信号通路，包括p38丝裂原活化蛋白激酶（p38 MAPK）、核因子κB（NF-κB）、肿瘤坏死因子（TNF）-α等，这些进一步促进了多种癌症中不受控制的增殖、生长、转移、血管生成、耐药性以及细胞凋亡逃避。在本综述中，讨论了糖基化和去糖基化在调节参与癌症进展的多个信号级联反应中的作用的平衡概述。此外，我们强调了去糖基化酶果糖胺-3-激酶（FN3K）在Nrf2驱动的癌症中的功能作用。FN3K的活性归因于其使Nrf2去糖基化的能力，Nrf2是细胞氧化应激的主要调节因子。FN3K是一种独特的蛋白质，通过磷酸化各种蛋白质（如Nrf2）中的碱性氨基酸赖氨酸和精氨酸来介导去糖基化。去糖基化的Nrf2是稳定的，并与小肌肉腱膜纤维肉瘤（sMAF）蛋白结合，从而激活细胞抗氧化机制以保护细胞免受氧化应激。Nrf2激活提供的这种细胞保护，一方面防止正常细胞转化为癌细胞；然而，另一方面，它不仅帮助癌细胞在缺氧条件下存活，而且还能使其免受各种化学和放射治疗。因此，Nrf2的激活类似于一把双刃剑，如果控制不当，可能导致许多实体瘤的发展。因此，需要开发新型小分子调节剂/植物化学物质，它们可以调节FN3K活性，从而将Nrf2维持在受控的激活状态。
