Biogenic polyamines spermine and spermidine are the oligocations that are present in cells at high concentrations and that regulate cell growth and differentiation. Polyamine concentrations are carefully maintained by coordinated control over the enzymes of their biosynthesis and catabolism. However, mechanisms of regulation of several key polyamine-metabolizing enzymes remain poorly studied.
We previously described that ornithine decarboxylase (ODC) and spermidine/spermine-N1-acetyltransferase (SSAT) are regulated by the redox-sensitive Nrf2 transcription factor, thus linking this metabolic system with oxidative stress (Smirnova et al, Biochimie 2012). This mechanism account for transient induction of these enzymes during hepatitis C virus infection (Smirnova et al, BBRC 2017).
Spermine oxidase (SMO/SMOX) and acetylpolyamine oxidase (APAO/PAOX) are the perspective goals for the development of antiviral agents, as our data indicate that their inhibitor MDL72.527 displays antiviral activity towards RNA viruses (Patent RU2667123C1 -2018; Patent RU2761565C1 – 2020). Moreover, this compounds was shown to overcome resistance of leukemia cells to anticancer agent doxorubicin, conferred by human cytomegalovirus (Fedorova et al, Biochimie 2019).
APAO is considered a peroxisomal enzyme that is transiently expressed and that catalyzes a non-rate-limiting step of polyamine catabolism. However, transcription rates of its gene in multiple cell lines remain very low. We have shown that this gene is almost not expressed and PAOX activity is not detected in various tumor cell lines with the exceptions of few low-passage glioblastoma cells. Induction of SSAT that generates PAOX substrates leads to decreased total polyamine pool with little back-conversion or accumulation of acetylated polyamines. It indicates that acetylated spermine and spermidine are predominantly secreted from cells (Ivanova et al, Cells 2024).
Our current goal is to identify mechanism of polyamine efflux.
