Among characteristic properties of cancers, there is their increased glycolytic activity.Contrary to normal cells, neoplastic cells use anaerobic glycolysis, even when a sufficient amount of oxygen is available. The intensity of the process is associated with a considerable demand for energy in the form of ATP. Akt, which - acting through the mTOR pathway - activates the HIF-1 factor, which in turn activates hexokinase that participates in glucose phosphorylation, stimulates the transport of glucose to cells via increasing glucose transporters (GLUT) and activates lactate dehydrogenase (which transforms pyruvate to lactate). Chitosan, as well as products of its degradation - oligochitosans - contribute to inhibiting the activity of the Akt kinase, and thus contribute to inhibiting excessive glycolytic activity of Ehrlich ascites tumor (EAT) cells and to decreasing proliferation of these cells.
Preliminary studies of proliferation of Ehrlich ascites tumor (EAT) cells and normal mammary gland epithelial cells have demonstrated the process to be inhibited by degradation products of microcrystalline chitosan, i.e. oligomers. Inhibition of proliferation has been also accompanied by a decreased activity of the M2 pyruvate kinase (PK) isoenzyme in nucleoplasm, what may indicate the role of this enzyme in regulation of tumor cell proliferation. Determinations of nitrogen oxide in tumor and normal cells point to a higher level of this endogenous effector in normal cells. An increase of nitrogen oxide levels in Ehrlich ascites tumor cells effected by chitosan oligomers may indicate increased nitrosylation, and particularly an increased amount of compounds containing sulfhydryl groups and their participation in regulation of nucleoplasm M2 PK isoenzyme activity. Chitosan oligomers have smaller molecules as compared to microcrystalline chitosan and for this reason appear to be more effective than the latter in acting upon the negatively charged cell membrane surfaces, thus contributing to proliferation inhibition.
Isoenzyme M2 pyruvate kinase, which is a marker of cancer transformation, can take both tetramer (cytosol) and dimer (nucleus) forms. The former is responsible for ATP synthesis, and the latter demonstrates histone H1 kinase activity. Regulation of the expression of pyruvate kinase through which Akt controls the expression of genes involved in Ehrlich ascites tumour (EAT) cell proliferation, migration and death, also involves cross-talk with the other signalling pathways, transcription factors and co-regulatory proteins such as β-catenin and c-Myc. Treatment of EAT cells with chitosans significantly reduced their proliferation (by 45-60%), expression of nuclear β-catenin, c-Myc as well as cell migration. After 48–72 hours of treatment of the cell with oligochitosans, lower levels of p-Akt were detected. Simultaneously, decreased expression of isoenzyme M2 PK protein levels was observed. The dimeric form (nucleus) can participate in H1 histone phosphorylation, which contributes to increased EAT cell proliferation.
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