Antizyme inhibitor 1: a potential carcinogenic molecule

Abstract

Polyamines are multivalent and organic cations essential for cellular growth, proliferation, differentiation, and apoptosis. Increased levels of polyamines are closely associated with numerous forms of cancer. An autoregulatory circuit composed of ornithine decarboxylase (ODC), antizyme (AZ) and antizyme inhibitor (AZI) govern the intracellular level of polyamines. Antizyme binds with ODC to inhibit ODC activity and to promote the ubiquitin‐independent degradation of ODC. Antizyme inhibitor binds to AZ with a higher affinity than ODC. Consequently, ODC is released from the ODC–AZ complex to rescue its activity. Antizyme inhibitor increases the ODC activity to accelerate the formation of intracellular polyamines, triggering gastric and breast carcinogenesis as well as hepatocellular carcinoma and esophageal squamous cell carcinoma development. Antizyme inhibitor 1 (AZIN1), a primary member of the AZI family, has aroused more attention because of its contribution to cancer. Even though its conformation is changed by adenosine‐to‐inosine (A→I) RNA editing, it plays an important role in tumorigenesis through regulating intracellular polyamines. Encouragingly, AZIN1 has been revealed to have an additional function outside the polyamine pathway so as to bypass the deficiency of targeting the polyamine biosynthetic pathway, promising to become a critical target for cancer therapy. Here, we review the latest research advances into AZIN1 and its potential contribution to carcinogenesis.

Inhibition of the aryl hydrocarbon receptor/polyamine biosynthesis axis suppresses multiple myeloma

“…AHR is a direct transcriptional activator of ODC1 and AZIN1. ODC1 and AZIN1 have been shown to have protumorigenic functions (12)(13)(14), and anti-polyamine agents have long been under consideration as chemotherapeutic agents, although none is currently in clinical use (2). Thus, a therapeutic strategy aimed at the simultaneous inhibition of ODC1 and AZIN1 may prove beneficial.…”

“…With the exception of the transcription factors MYC (8)(9)(10) and SP1 (11), little is known about the transcriptional regulation of polyamine biosynthesis. Importantly, although both ODC1 and AZIN1 have been shown to have protumorigenic functions (12)(13)(14) and anti-polyamine agents have been under consideration as chemotherapy, none is currently in clinical use (2).…”

Insights into the non-mitotic functions of Aurora kinase A: more than just cell division

“…On the other hand, work performed in cell culture models showed that the Aurora A kinase interacting protein 1 (AURKAIP1) enhances the binding of Antizyme1 (AZ1) on AURKA [62][63][64]. AZ1 is an enzyme belonging to the polyamine biosynthesis pathway, and it is known to regulate ubiquitin-independent protein degradation programs [65]. According to its enzymatic function, AZ1 promotes the ubiquitin-independent, but proteasome-dependent degradation of AURKA after mitotic exit [63,64].…”

Post-Transcriptional Control of RNA Expression in Cancer

“…One example is ADAR-1 editing of the Antizyme Inhibitor 1 (AZIN1), which leads to a serine-to-glycine substitution at residue 367 [41]. AZIN1 is an inactive homolog of ornithine decarboxylase (ODC) that competitively binds to antizymes [42]. ADAR-1 editing increases AZIN1 affinity to antizyme, leading to a decrease in ODC antizyme-mediated degradation and promoting polyamines biosynthesis, with consequent cell proliferation and a more aggressive behavior in hepatocellular carcinoma cells [41].…”