Polyamines in cell growth and cell death: molecular mechanisms and therapeutic applications

Abstract

Polyamines are aliphatic cations with multiple functions and are essential for life. Cellular polyamine levels are regulated by multiple pathways such as synthesis from amino acid precursors, cellular uptake mechanisms that salvage polyamines from diet and intestinal microorganisms, as well as stepwise degradation and efflux. Investigations using polyamine biosynthetic inhibitors indicate that alterations in cellular polyamine levels modulate normal and cancer cell growth. Studies using transgenic mice overexpressing polyamine biosynthetic enzymes support a role of polyamines in carcinogenesis. Many, if not all, signal transduction pathways intersect with polyamine biosynthetic pathways and the regulation of intracellular polyamine levels. Direct binding of polyamines to DNA and their ability to modulate DNA-protein interactions appear to be important in the molecular mechanisms of polyamine action in cell proliferation. Consistent with the role of polyamines as facilitators of cell growth, several studies have shown their ability to protect cells from apoptosis. However, polyamines also have a role in facilitating cell death. The basis of these diverse cellular responses is currently not known. Cell death response might be partly mediated by the production of hydrogen peroxide during polyamine catabolism. In addition, the ability of polyamines to alter DNA-protein and protein-protein interactions might be disruptive to cellular functions, when abnormally high levels are accumulated due to defects in polyamine catabolic or efflux pathways. A large body of data indicates that polyamine pathway can be a molecular target for therapeutic intervention in several types cancers. Inhibitors of biosynthesis, polyamine analogues as well as oligonucleotide/polyamine analogue combinations are promising drug candidates for chemoprevention and/or treatment of cancer.

Regulation of estrogenic and nuclear factor κB functions by polyamines and their role in polyamine analog-induced apoptosis of breast cancer cells

“…Polyamines are intracellular polycationic molecules found in all living cells (Pegg and McCann, 1982;Tabor and Tabor, 1984;Thomas and Thomas, 2001). Polyamine levels are highly regulated by biosynthetic and metabolizing enzymes, and an elevated cellular polyamine concentration has been linked to the initiation and progression of cancer (Hibshoosh et al, 1991;O'Brien et al, 1992;Smith et al, 1998).…”

Charge inversion accompanies DNA condensation by multivalent ions

“…The condensation of stiff, highly charged DNA molecules into compact structures by condensing agents ranging from multivalent ions 1 to small cationic proteins 2,3 is of major biological and therapeutic importance 4,5 , yet the underlying microscopic mechanism remains poorly understood 1,6-9 . It has been proposed 7,10 that DNA condensation is a purely electrostatic phenomenon driven by the existence of a strongly correlated liquid (SCL) of counterions at the DNA surface.…”

Arginine Decarboxylase expression, polyamines biosynthesis and reactive oxygen species during organogenic nodule formation in hop

“…Studies in mammalian cells showed direct binding of PAs to nucleic acids and ability to modulate their conformation and interaction with proteins, playing a role in cellular signaling. 4 At different phases of mitosis in Scots pine related to the expression of morphogenic capacity of the tissue in culture and protection against oxidative stress.…”

“…1 They have been implicated in a wide range of biological processes, including cell growth and division, stabilization of nucleic acids and membranes, protein synthesis and chromatin function, and biotic and abiotic stresses responses. [2][3][4][5] The most common PAs are spermidine and spermine, together with their diamine precursor putrescine. The biosynthesis of PAs is controlled in plants primarily by three enzymes: arginine decarboxylase (ADC; EC 4.1.…”