Tulluri Vennela, Nemmara Venkatesh V
Department of Chemistry and Biochemistry, Rowan University, Glassboro, NJ 08028, USA.
Onco Targets Ther. 2021 Jan 25;14:667-682. doi: 10.2147/OTT.S281157. eCollection 2021.
Polyamines are multivalent organic cations essential for many cellular functions, including cell growth, differentiation, and proliferation. However, elevated polyamine levels are associated with a slew of pathological conditions, including multiple cancers. Intracellular polyamine levels are primarily controlled by the autoregulatory circuit comprising two different protein types, Antizymes (OAZ) and Antizyme Inhibitors (AZIN), which regulate the activity of the polyamine biosynthetic enzyme ornithine decarboxylase (ODC). While OAZ functions to decrease the intracellular polyamine levels by inhibiting ODC activity and exerting a negative control of polyamine uptake, AZIN operates to increase intracellular polyamine levels by binding and sequestering OAZ to relieve ODC inhibition and to increase polyamine uptake. Interestingly, OAZ and AZIN exhibit autoregulatory functions on polyamine independent pathways as well. A growing body of evidence demonstrates the dysregulation of AZIN expression in multiple cancers. Additionally, RNA editing of the transcript results in a "gain-of-function" phenotype, which is shown to drive aggressive tumor types. This review will discuss the recent advances in AZIN's role in cancers via aberrant polyamine upregulation and its polyamine-independent protein regulation. This report will also highlight AZIN interaction with proteins outside the polyamine biosynthetic pathway and its potential implication to cancer pathogenesis. Finally, this review will reveal the protein interaction network of AZIN isoforms by analyzing three different interactome databases.
多胺是许多细胞功能所必需的多价有机阳离子，包括细胞生长、分化和增殖。然而，多胺水平升高与一系列病理状况相关，包括多种癌症。细胞内多胺水平主要由包含两种不同蛋白质类型的自动调节回路控制，即抗酶（OAZ）和抗酶抑制剂（AZIN），它们调节多胺生物合成酶鸟氨酸脱羧酶（ODC）的活性。虽然OAZ通过抑制ODC活性来降低细胞内多胺水平，并对多胺摄取施加负调控，但AZIN通过结合和隔离OAZ以解除ODC抑制并增加多胺摄取来提高细胞内多胺水平。有趣的是，OAZ和AZIN在多胺非依赖途径上也表现出自动调节功能。越来越多的证据表明AZIN表达在多种癌症中失调。此外，该转录本的RNA编辑导致一种“功能获得”表型，已证明这种表型会驱动侵袭性肿瘤类型。本综述将讨论AZIN通过异常的多胺上调在癌症中的作用及其多胺非依赖的蛋白质调节方面的最新进展。本报告还将强调AZIN与多胺生物合成途径之外的蛋白质的相互作用及其对癌症发病机制的潜在影响。最后，本综述将通过分析三个不同的相互作用组数据库揭示AZIN亚型的蛋白质相互作用网络。
