Objectives: To investigate the effects of betaine on HeLa cell growth and apoptosis and molecular mechanisms. Materials and Methods: Concentrations of 0.1, 1.0, 5.0, 20.0, 100.0 mg/ml of betaine were used to evaluate the anticancer efficacy for HeLa cells respectively, and MCF-10A was also detected as a normal diploid cell control. Results: We found that proliferation of HeLa cells was inhibited significantly upon exposure to increasing betaine levels with the MTT test (p<0.05). The percentage of S phase cells in the low dose groups (< 5mg/ml) were distinctly higher than in high dose groups, and the rates of Sub-G1 phase were the opposite (p<0.01); A high concentration of betaine (>5.0mg/ml) significantly promoted the apoptosis of HeLa cells (p<0.01). SOD activities of the low dose groups were slightly higher than the control group (p<0.05) and there were obvious synchronicity and correlation among the expression of promoting apoptosis genes Bax, P53, Caspase 3 and apoptosis suppression gene Bcl-2. In response to an apoptosis-inducing stimulus, p53 and cyclin D1 could be activated with blockage of the cell cycle at G1/S or S/G2 checkpoints. Conclusions: Our data showed that betaine could promote HeLa cells proliferation in vitro at low concentrations.In contrast, high concentrations could significantly inhibit cell growth and migration, and induce apoptosis of HeLa cells through caspase 3 signaling and further promoted necrosis. This might imply that betaine exhibits tumoricidal effects and acts as a biological response modifier in cancer treatment by inducing apoptosis and cell cycle arrest in a dose and time-dependent manner.
Cyclosporine-A (CsA) stimulates heme oxygenase-1 (HO-1) expression in the gingiva, but the regulation and the role of HO-1 in gingival overgrowth are not well-understood. HO-1 is regulated by several transcription factors, such as nuclear factor-κB (NF-κB) and nuclear factor erythroid-2-related factor 2 (Nrf-2). The aim of this study was to examine the role of Nrf-2 in the regulation of CsA-stimulated HO-1 expression in human gingival fibroblasts. Nrf-2 siRNA (siNrf-2), NF-κB, kinase inhibitors, and sulforaphane (SFN) were used to examine the nuclear translocation of Nrf-2 and expression of HO-1 and transforming growth factor-β1 (TGF-β1) in cells. Treatment with siNrf-2, but not with an NF-κB inhibitor, reduced CsA-stimulated HO-1 mRNA expression. ERK inhibition significantly decreased CsA-stimulated Nrf-2 nuclear translocation and HO-1 mRNA expression. Pre-treatment with SFN showed that HO-1 plays a role in attenuating CsA-mediated TGF-β1 expressions. These findings suggest that CsA-stimulated HO-1 expression is mediated through the activation of ERK, and that Nrf-2 plays a protective role against CsA-induced gingival fibrosis by modulating collagen turnover-related genes.
Although nucleolar protein nucleostemin (NS) is essential for cell proliferation and early embryogenesis and expression has been observed in some types of human cancer and stem cells, the molecular mechanisms involved in mediation of cell proliferation and cell cycling remains largely elusive. The aim of the present study was to evaluate NS as a potential target for gene therapy of human breast carcinoma by investigating NS gene expression and its effects on SKBR-3 cell proliferation and apoptosis. NS mRNA and protein were both found to be highly expressed in all detected cancer cell lines. The apoptotic rate of the pcDNA3.1-NS-Silencer group (12.1-15.4±3.8%) was significantly higher than those of pcDNA3.1-NS (7.2-12.0±1.7%) and non-transfection groups (4.1-6.5±1.8%, P<0.01). MTT assays showed the knockdown of NS expression reduced the proliferation rate of SKBR-3 cells significantly. Matrigel invasion and wound healing assays indicated that the number of invading cells was significantly decreased in the pcDNA3.1-NS-siRNA group (P<0.01), but there were no significant difference between non-transfected and over-expression groups (P>0.05). Moreover, RNAi-mediated NS downregulation induced SKBR-3 cell G1 phase arrest, inhibited cell proliferation, and promoted p53 pathway-mediated cell apoptosis in SKBR-3 cells. NS might thus be an important regulator in the G2/M check point of cell cycle, blocking SKBR-3 cell progression through the G1/S phase. On the whole, these results suggest NS might be a tumor suppressor and important therapeutic target in human cancers.
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