Abstract
Differentiation therapy by induction of tumor cells is an important method in the treatment of hematological cancers such as leukemia. Tumor cell differentiation ends cancer cells' immortality, thus stopping cell growth and proliferation. In our previous study, we found that fucose-containing polysaccharide fraction F3 extracted from Ganoderma lucidum can bring about cytokine secretion and cell death in human leukemia THP-1 cells. This prompted us to further investigate on how F3 induces the differentiation in human leukemia cells. We integrated time-course microarray analysis and network modeling to study the F3-induced effects on THP-1 cells. In addition, we determined the differentiation effect using Liu's staining, nitroblue tetrazolium (NBT) reduction assay, flow cytometer, western blotting and Q-PCR. We also examined the modulation and regulation by F3 during the differentiation process. Dynamic gene expression profiles showed that cell differentiation was induced in F3-treated THP-1 cells. Furthermore, F3-treated THP-1 cells exhibited enhanced macrophage differentiation, as demonstrated by changes in cell adherence, cell cycle arrest, NBT reduction and expression of differentiation markers including CD11b, CD14, CD68, matrix metalloproteinase-9 and myeloperoxidase. In addition, caspase cleavage and p53 activation were found to be significantly enhanced in F3-treated THP-1 cells. We unraveled the role of caspases and p53 in F3-induced THP-1 cells differentiation into macrophages. Our results provide a molecular explanation for the differentiation effect of F3 on human leukemia THP-1 cells and offer a prospect for a potential leukemia differentiation therapy.
Highlights
Ganoderma lucidum (Reishi or Ling-Zhi) is more than just an ordinary fungus; it has long been used in traditional Chinese medicinal remedies and for promotion of health and longevity, in many Asian countries
We found that fucose-containing polysaccharide fraction F3 extracted from Ganoderma lucidum can bring about cytokine secretion and cell death in human leukemia THP-1 cells
G. lucidum polysaccharides have been used as active compounds for immuno-modulation and to display anti-tumor activity; little attention has been paid to its effect on the process of cancer cell differentiation [18]
Summary
Ganoderma lucidum (Reishi or Ling-Zhi) is more than just an ordinary fungus; it has long been used in traditional Chinese medicinal remedies and for promotion of health and longevity, in many Asian countries. Recent studies showed that G. lucidum is used to prevent or treat various human diseases such as allergy, hepatopathy, hypertension and cancer [1,2,3]. Previous evidences showed that polysaccharides extracted from G. lucidum have potential anti-cancer effects through the inhibition of cancer cell growth, induction of cell differentiation and suppression of angiogenesis [2, 3]. The biologically active compounds originally isolated and purified from G. lucidum were identified as polysaccharides, and the main fraction was designated as F3. Since F3 activates a wide range of cellular responses, a systematic investigation into its molecular mechanisms would require a large-scale and genome-wide technology, for example, using microarray analysis to explore the cellular alteration and molecular disturbances induced by F3
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