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Role of Antizyme Inhibitor Proteins in Cancers and Beyond

Authors Tulluri V, Nemmara VV

Received 10 September 2020

Accepted for publication 5 November 2020

Published 25 January 2021 Volume 2021:14 Pages 667—682

DOI https://doi.org/10.2147/OTT.S281157

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Dr Leo Jen-Liang Su


Vennela Tulluri, Venkatesh V Nemmara

Department of Chemistry and Biochemistry, Rowan University, Glassboro, NJ 08028, USA

Correspondence: Venkatesh V Nemmara
Department of Chemistry and Biochemistry, Rowan University, 201 Mullica Hill Road, Glassboro, NJ 08028, USA
Tel +1 856-256-5460
Email nemmara@rowan.edu

Abstract: 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 Azin1 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.

Keywords: polyamine, ornithine decarboxylase, antizyme inhibitor, antizyme, putrescine, spermine, spermidine, mRNA editing, 26S proteasome, degradation, ubiquitin-independent, protein interactome

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