Nepal Manoj, Ma Chi, Xie Guoxiang, Jia Wei, Fei Peiwen
University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
Graduate Program of Molecular Biosciences and Bioengineering, University of Hawaii, Honolulu, HI 96822, USA.
Aging (Albany NY). 2018 Jun 21;10(6):1506-1522. doi: 10.18632/aging.101487.
Given importance of 22-Fanconi Anemia (FA) proteins together to act in a signaling pathway in preventing deleterious clinical symptoms, e.g. severe bone marrow failure, congenital defects, an early onset of aging and cancer, studies on each FA protein become increasingly attractive. However, an unbiased and systematic investigation of cellular effects resulting from each FA protein is missing. Here, we report roles of FA complementation C group protein (FANCC) in the protection from metabolic disorders. This study was prompted by the diabetes-prone feature displayed in FANCC knockout mice, which is not typically shown in patients with FA. We found that in cells expressing FANCC at different levels, there are representative alterations in metabolites associated with aging (glycine, citrulline, ornithine, L-asparagine, L-tyrosine, L-arginine, L-glutamine, L-leucine, L-isoleucine, L-valine, L-proline and L-alanine), Diabetes Mellitus (DM) (carbon monoxide, collagens, fatty acids, D-glucose, fumaric acid, 2-oxoglutaric acid, C3), inflammation (inosine, L-arginine, L-isoleucine, L-leucine, L-lysine, L-phenylalanine, hypoxanthine, L-methionine), and cancer ( L-methionine, sphingomyelin, acetyl-L-carnitine, L-aspartic acid, L-glutamic acid, niacinamide, phospho-rylethanolamine). We also found that FANCC can act in an FA-pathway-independent manner in tumor suppression. Collectively, featured-metabolic alterations are readouts of functional mechanisms underlying reduced tumorigenicity driven by FANCC, demonstrating close links among cancer, aging, inflammation and DM.
鉴于22种范可尼贫血（FA）蛋白共同作用于一个信号通路以预防有害临床症状（如严重骨髓衰竭、先天性缺陷、早衰和癌症）的重要性，对每种FA蛋白的研究变得越来越有吸引力。然而，目前缺少对每种FA蛋白所产生的细胞效应进行无偏倚且系统的研究。在此，我们报告了FA互补C组蛋白（FANCC）在预防代谢紊乱方面的作用。这项研究是由FANCC基因敲除小鼠表现出的糖尿病易患特征所引发的，而FA患者通常不会出现这种特征。我们发现，在表达不同水平FANCC的细胞中，与衰老相关的代谢物（甘氨酸、瓜氨酸、鸟氨酸、L - 天冬酰胺、L - 酪氨酸、L - 精氨酸、L - 谷氨酰胺、L - 亮氨酸、L - 异亮氨酸、L - 缬氨酸、L - 脯氨酸和L - 丙氨酸）、糖尿病（DM）（一氧化碳、胶原蛋白、脂肪酸、D - 葡萄糖、富马酸、2 - 氧代戊二酸、C3）、炎症（肌苷、L - 精氨酸、L - 异亮氨酸、L - 亮氨酸、L - 赖氨酸、L - 苯丙氨酸、次黄嘌呤、L - 蛋氨酸）和癌症（L - 蛋氨酸、鞘磷脂、乙酰 - L - 肉碱、L - 天冬氨酸、L - 谷氨酸、烟酰胺、磷酸乙醇胺）存在典型变化。我们还发现，FANCC可以通过一种不依赖FA通路的方式发挥肿瘤抑制作用。总的来说，特定的代谢改变是FANCC驱动的肿瘤发生能力降低的功能机制的读数，表明癌症、衰老、炎症和糖尿病之间存在密切联系。
