Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) wild-type is intrinsic resistance to EGFR-tyrosine kinase inhibitors (TKIs). In this study, we assessed whether the combination of bisdemethoxycurcumin (BDMC) and icotinib could surmount primary EGFR-TKI resistance in NSCLC cells and investigated its molecular mechanism. Results showed that the combination of BDMC and icotinib produced potently synergistic growth inhibitory effect on primary EGFR-TKI-resistant NSCLC cell lines H460 (EGFR wild-type and K-ras mutation) and H1781 (EGFR wild-type and Her2 mutation). Compared with BDMC or icotinib alone, the two drug combination induced more significant apoptosis and autophagy via suppressing EGFR activity and interaction of Sp1 and HDCA1/HDCA2, which was accompanied by accumulation of reactive oxygen species (ROS), induction of DNA damage, and inhibition of cell migration and invasion. ROS inhibitor (NAC) and autophagy inhibitors (CQ or 3-MA) partially reversed BDMC plus icotinib-induced growth inhibitory effect on the NSCLC cells. Meanwhile, co-treatment with NAC attenuated the two drug combination-induced autophagy, apoptosis, DNA damage and decrease of cell migration and invasion ability. Also, 3-MA or CQ can abate the combination treatment-induced apoptosis and DNA damage, suggesting that there is crosstalk between different signaling pathways in the effect produced by the combination treatment. Our data indicate that BMDC has the potential to improve the treatment of primary EGFR-TKI resistant NISCLC that cannot be controlled with single-target agent, such as icotinib.
Transforming growth factor β (TGF-β) is a polypeptide growth factor with various biological activities, and is widely distributed in various tissues. In mammals, TGF-β has three isoforms: TGF-β1, 2, and 3, of which TGF-β1 is most abundant in the TGF-β family. TGF-β1 is closely related to the occurrence and development of tumors. A large number of previous studies have shown that melatonin can inhibit a variety of malignancies. Thus, the aim of the present study was to investigate the role of TGF-β1 in the melatonin-mediated inhibition of the proliferation of gastric cancer cells in vitro and in vivo. TGF-β1 cytokine stimulation, anti-TGF-β1 neutralizing antibody blocking, siRNA TGF-β1 and other means were utilized to explore the role of TGF-β1 during the course of anti-gastric cancer by melatonin. The results showed that melatonin upregulated the expression of TGF-β1 in tumor tissues during the process of inhibiting gastric cancer tumor growth in vivo. Melatonin inhibited the proliferation of gastric cancer cells in vitro, accompanied by increased expression of TGF-β1 in a time-dependent manner. siRNA-mediated silencing of TGF-β1 and anti-TGF-β1 neutralizing antibody completely blocked the TGF-β1 pathway, which significantly antagonized the melatonin-mediated inhibition of the growth and proliferation of gastric cancer cells, and promoted G1 phase to S phase transformation of MFC cells. Our findings suggest that TGF-β1 is involved in the regulation of the proliferation of tumor cells. One of the ways in which melatonin inhibits the proliferation of gastric cancer cells is dependent on the TGF-β1 signaling pathway.
Abstract. The present study was performed to investigate the role of p38 mitogen-activated protein kinase (MAPK) in the resorption of herniated intervertebral discs in 30 rats. In the non-contained and p38 MAPK inhibition (p38i) groups, two coccygeal intervertebral discs (IVDs) were removed and wounded prior to relocation into the subcutaneous space of the skin of the back. In the contained group, the cartilage endplates maintained their integrity. Furthermore, SB203580 was injected intraperitoneally into the p38i group, whereas saline was injected into the other two groups. In the non-contained group, the weight of the relocated IVDs decreased to a greater extent over time when compared with the contained and p38i groups. Phosphorylated p38, tumor necrosis factor-α, and interleukin-1β were observed to exhibit higher expression levels in the non-contained group compared with the contained and p38i groups, at weeks 1 and 4 post-surgery. The expression level of caspase-3 and the densities of apoptotic disc cells were significantly higher in the non-contained group compared with the contained and p38i groups at 4 weeks post-surgery. In conclusion, p38 MAPK induces apoptosis in IVDs, while also accelerating the resorption of the relocated IVDs. Thus, p38 MAPK may be important in spontaneous resorption of IVDs.
In the process of enlarging of tumors, the dissolving tissue structures and remodeling endothelial cells for restoring gas exchange and nutritional support, further facilitate tumor cell invasion and metastasis. Activation of Ras plays a critical role in the development of esophageal squamous cell carcinoma (ESCC), but the underlying mechanisms remain poorly understood. We therefore investigated whether Ras guanyl-releasing protein 3 (RasGRP3), a Ras activator, could promote metastasis by inducing vascular regeneration and further epithelial-mesenchymal transition under nutrient stress (NS). In the present study, we explored that the accumulation of RasGRP3 regulated vascular endothelial growth factor-A production, co-stimulated Notch pathway with high expression of Notch intracellular domain (NICD) and Hes1. Moreover, ESCC cells under NS increased the expression of vimentin, Snail, Slug and MMP9 proteins; while inhibition of Notch activation by DAPT (a γ-secretase inhibitor) or RasGRP3-targeted RNA interference prevented from the effect. In conclusion, these findings provide a new insight into the upregulation of RasGRP3 involved in Notch pathway activation in the development of ESCC, especially under nutrient deprivation.
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