Abstract
Polyamines are essential growth factors that have a positive role in cancer cell growth. Their metabolic pathway and the diverse enzymes involved have been studied in depth in multiple organisms and cells. Polyamine transport also contributes to the intracellular polyamine content but this is less well-studied in mammalian cells. As the polyamine transporters could provide a means of selective drug delivery to cancer cells, a greater understanding of polyamine transport and its regulation is needed. In this study, transport of polyamines and polyamine content was measured and the effect of modulating each was determined in human colorectal cancer cells. The results provide evidence that upregulation of polyamine transport depends on polyamine depletion and on the rate of cell growth. Polyamine transport occurred in all colorectal cancer cell lines tested but to varying extents. The cell lines with the lowest basal uptake showed the greatest increase in response to polyamine depletion. Kinetic parameters for putrescine and spermidine suggest the existence of two separate transporters. Transport was shown to be a saturable but non-polarised process that can be regulated both positively and negatively. Using the polyamine transporter to deliver anticancer drugs more selectively is now a reality, and the ability to manipulate the polyamine transport process increases the possibility of using these transporters therapeutically.
Highlights
Polyamines are small molecules found in all eukaryotic cells and are important in several crucial biological processes ranging from nucleic acid stabilisation to cell proliferation [1,2,3,4].Highly proliferating tissue and cells, as found in cancer, require a constant provision of polyamines to support their continuous proliferation
It is known that treatment with DFMO can upregulate polyamine transport in mammalian cells but the time needed to achieve this and the temporal relationship to polyamine depletion is not clear
In SW480 human colorectal cancer cells, the uptake of putrescine and spermidine was measured in exponentially growing cells and was shown to be time-dependent
Summary
Proliferating tissue and cells, as found in cancer, require a constant provision of polyamines to support their continuous proliferation. Many types of human cancer have been shown to have intracellular polyamine contents 4- to 6-fold greater than the corresponding normal tissue [3]. Intracellular concentrations are determined by a combination of de novo synthesis and transport of polyamines into and out the cell with each part being regulated carefully to maintain optimum cell growth and/or survival. Active transport is mediated by carrier proteins, which are present, to various extents, on the surface of cells. It requires energy and can be modulated depending on the needs of the cell. Passive transport is generally slower and can occur without carrier molecules via pores in the membrane [5]
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