Abstract
Cancer tissues contain cancer stem cells (CSCs), which play important roles in cancer metastasis. However, the mechanisms through which cancer cells dedifferentiate into stem cells have not yet been elucidated. In this study, the effects of high concentrations of polyamines produced in cancer cells on dedifferentiation were examined. The results showed that when normal human fibroblasts were cultured with high concentrations of spermine, the obtained polyamine-induced cells expressed alkaline phosphatase and marker proteins of pluripotent stem cells, although apoptosis occurred in most cells. In contrast, another polyamine-induced stem (PIS) cell line (Spe-2 PIS cells), obtained by culture in medium containing Rock, p53, and Bax inhibitors plus spermine, did not show signs of apoptosis. These Spe-2 PIS cells expressed marker proteins of pluripotent stem cells and differentiated into cardiomyocytes, brown adipocytes, and nerve cells. These results suggest that a high concentration of spermine, which often induces apoptosis in normal cells, has the capacity to dedifferentiate somatic cells into pluripotent stem cells and may be associated with the dedifferentiation of cancer cells, which continuously produce high concentrations of spermine. Moreover, the procedure to obtain Spe-2 PIS cells, which is simple and efficient, may have potential applications in regenerative medicine.
Highlights
Polyamines are aliphatic amines containing more than two amino groups; putrescine, spermidine, and spermine are the primary polyamines in mammals [1,2,3]
Preliminary experiments showed that the growth rate of TIG-1-20 cells gradually decreased during approximately 2 months of subculture and plateaued at population doubling level (PDL) 50-55, suggesting that the TIG-1-20 cells used in this study were normal
The results showed that cells cultured in the presence of high concentrations of putrescine, spermidine, and spermine (10 - 60 μM) showed changes in shape, containing many small particles, and detached from the dishes; such changes were not observed at lower concentrations
Summary
Polyamines are aliphatic amines containing more than two amino groups; putrescine, spermidine, and spermine are the primary polyamines in mammals [1,2,3]. Because of their important physiological roles, the concentrations of polyamines are strictly controlled in cells via various metabolic pathways [8]. The activities of AdoMetDC, ODC, and SAT are strictly controlled to maintain polyamines at low levels under normal conditions and are enhanced only when polyamines at higher levels are necessary These mechanisms are disrupted in cancer cells, which continuously produce high amounts of polyamines, such as spermidine and spermine [9, 10]. Consistent with this, patients with cancer exhibit high levels of acetylpolyamines in the blood, and the levels of these compounds can be normalized after excision of the tumor
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