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Published on: August 2, 2021
Spermine acts as a negative regulator of macrophage differentiation in human myeloid leukemia cells
Igor M Gavin1, David Glesne, Yong Zhao
1Biochip Technology Center, Argonne National Laboratory, Argonne, Illinois, USA.
Abstract:
The role of putrescine, spermidine and spermine in phorbol 12-myristate-13-acetate (PMA)-induced macrophage differentiation was examined in human HL-60 and U-937 myeloid leukemia cells. Unlike other polyamines, spermine affected this differentiation by acting as a negative regulator. This negative regulation was established by showing that the PMA-induced macrophage phenotype, but not PMA-associated replication arrest, was abrogated (a) by replenishing the PMA-evoked decrease in cellular spermine levels with this polyamine from an exogenous source and (b) by blocking PMA-induced expression of the polyamine catabolic enzyme N(1)-spermidine/spermine acetyltransferase (SSAT) with antisense oligonucleotides in the presence of low substrate level. The PMA-evoked reduction in cellular spermine appears to result from an increase in the activity of SSAT and a decrease in the activity of ornithine decarboxylase, the polyamine biosynthetic enzyme. To a degree, these changes are due to corresponding changes in the expression of the genes that code for these enzymes. When cell differentiation is initiated, SSAT expression is increased after PMA-evoked activation of protein kinase C-beta. The present studies raise the possibility that agents able to reduce spermine levels in patients' myeloid leukemia cells may enhance the activity of differentiation therapy drugs for this type of leukemia.
Insights
Spermine negatively regulates phorbol 12-myristate-13-acetate (PMA)-induced macrophage differentiation in leukemia cells. Reducing spermine levels may enhance differentiation therapy for myeloid leukemia.
Area of Science:
- Cell Biology
- Biochemistry
- Molecular Biology
Background:
- Polyamines like putrescine, spermidine, and spermine are crucial for cell growth and differentiation.
- Phorbol 12-myristate-13-acetate (PMA) is a potent inducer of macrophage differentiation in myeloid leukemia cell lines.
Purpose of the Study:
- To investigate the specific role of spermine in PMA-induced macrophage differentiation.
- To elucidate the regulatory mechanisms by which spermine influences this process.
Main Methods:
- Utilized human HL-60 and U-937 myeloid leukemia cell lines.
- Examined the effects of exogenous spermine replenishment and N(1)-spermidine/spermine acetyltransferase (SSAT) inhibition on PMA-induced differentiation.
- Assessed changes in polyamine levels, enzyme activities (SSAT, ornithine decarboxylase), and gene expression.
Main Results:
- Spermine acts as a negative regulator of PMA-induced macrophage differentiation, unlike other polyamines.
- Restoring cellular spermine levels or inhibiting SSAT activity abrogated the PMA-induced differentiation phenotype.
- PMA treatment decreased cellular spermine by increasing SSAT activity and decreasing ornithine decarboxylase activity, partly via gene expression changes.
Conclusions:
- Spermine's reduction, mediated by SSAT activation and ornithine decarboxylase inhibition, is a key event in PMA-induced myeloid leukemia cell differentiation.
- Targeting spermine levels could potentially enhance the efficacy of differentiation therapy for myeloid leukemia.
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