CBP plays a central role in coordinating and integrating multiple signaling pathways. Competition between NF-kappaB and p53 for CBP is a crucial determinant of whether a cell proliferates or undergoes apoptosis. However, how the CBP-dependent crosstalk between these two transcription factors is regulated remains unclear. Here, we show that IKKalpha phosphorylates CBP at serine 1382 and serine 1386 and consequently increases CBP's HAT and transcriptional activities. Importantly, such phosphorylation enhances NF-kappaB-mediated gene expression and suppresses p53-mediated gene expression by switching the binding preference of CBP from p53 to NF-kappaB, thus promoting cell growth. The CBP phosphorylation also correlates with constitutive IKKalpha activation in human lung tumor tissue compared with matched nontumor lung tissue. Our results suggest that phosphorylation of CBP by IKKalpha regulates the CBP-mediated crosstalk between NF-kappaB and p53 and thus may be a critical factor in the promotion of cell proliferation and tumor growth.
Aim: To investigate whether sphingosine-1-phosphate (S1P), a potent angiogenic factor, induced vascular endothelial growth factor-C (VEGF-C) expression in endothelial cells in vitro and to examine its underlying mechanisms. Methods: Human umbilical vein endothelial cells (HUVECs) were examined. VEGF-C mRNA expression in the cells was assessed using real-time PCR. VEGF-C protein and FGFR-1 phosphorylation in the cells were measured with ELISA. RNA interference was used to downregulate the expression of matrix metalloproteinase-2 (MMP-2), fibroblast growth factor-1 (FGF-1) and FGF receptor-1 (FGFR-1). Results: Incubation of HUVECs with S1P (1, 5, and 10 μmol/L) significantly increased VEGF-C expression. The effect was blocked by pretreatment with the MMP inhibitor GM6001 or the FGFR inhibitor SU5402, but not the EGFR inhibitor AG1478. The effect was also blocked in HUVECs that were transfected with FGFR-1 or MMP-2 siRNA. Furthermore, incubation of HUVECs with S1P (5 μmol/L) significantly increased FGFR-1 phosphorylation, which was blocked by GM6001. Moreover, knockdown of FGF-1, not FGF-2, in HUVECs with siRNAs, blocked S1P-induced VEGF-C expression. Conclusion: S1P induces VEGF-C expression through a MMP-2/ FGF-1/FGFR-1-dependent pathway in HUVECs.
When treating cancer with chemotherapy, serious side effects are caused by the inability of the drug to be solely delivered to the tumor. As a result, a portion of the drug agents is inevitably delivered elsewhere and destroy normal cells. We report the first results on combining ultrasound with an aptamer-doxorubicin conjugate to treat cancer cells. Enhancement of therapeutic effects combined with a reduction in side effects indicates the potential of this approach. Although many studies have noted that ultrasound can enhance drug delivery, ultrasound has not addressed the goal of reducing side effects. To both reduce side effects and enhance the efficiency of killing cancer cells, this study mainly uses a specially targeted aptamer conjugated to the anticancer drug doxorubicin (DOX), which was applied in combination with ultrasound for cancer treatment. We also compared the results between cancer and normal cell lines to explore the targeting effect of the aptamer. Both breast cancer cells (MCF-7) and breast cells (MCF-10A) were used for the experiments. The results show that the aptamer conjugated to an anticancer drug can be used to target cancer cells and ultrasound can enhance drug delivery. This method can significantly reduce the side effects of the anticancer drug and achieve favorable therapeutic effects. Aptamer, cancer, drug delivery, ultrasound.
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