Recent studies have demonstrated that the Wnt/β-catenin signaling plays an important role in stem cell aging. However, the mechanisms of cell senescence induced by Wnt/β-catenin signaling are still poorly understood. Our preliminary study has indicated that activated Wnt/β-catenin signaling can induce MSC aging. In this study, we reported that the Wnt/β-catenin signaling was a potent activator of reactive oxygen species (ROS) generation in MSCs. After scavenging ROS with N-acetylcysteine, Wnt/β-catenin signaling-induced MSC aging was significantly attenuated and the DNA damage and the expression of p16(INK4A), p53, and p21 were reduced in MSCs. These results indicated that the Wnt/β-catenin signaling could induce MSC aging through promoting the intracellular production of ROS, and ROS may be the main mediators of MSC aging induced by excessive activation of Wnt/β-catenin signaling.
Aim: To examine the anti-cancer effects of chamaejasmenin B and neochamaejasmin C, two biflavonones isolated from the root of Stellera chamaejasme L (known as the traditional Chinese herb Rui Xiang Lang Du) in vitro. Methods: Human liver carcinoma cell lines (HepG2 and SMMC-7721), a human non-small cell lung cancer cell line (A549), human osteosarcoma cell lines (MG63, U2OS, and KHOS), a human colon cancer cell line (HCT-116) and a human cervical cancer cell line (HeLa) were used. The anti-proliferative effects of the compounds were measured using SRB cytotoxicity assay. DNA damage was detected by immunofluorescence and Western blotting. Apoptosis and cell cycle distribution were assessed using flow cytometry analysis. The expression of the related proteins was examined with Western blotting analysis. Results: Both chamaejasmenin B and neochamaejasmin C exerted potent anti-proliferative effects in the 8 human solid tumor cell lines. Chamaejasmenin B (the IC 50 values ranged from 1.08 to 10.8 μmol/L) was slightly more potent than neochamaejasmin C (the IC 50 values ranged from 3.07 to 15.97 μmol/L). In the most sensitive A549 and KHOS cells, the mechanisms underlying the anti-proliferative effects were characterized. The two compounds induced prominent expression of the DNA damage marker γ-H2AX as well as apoptosis. Furthermore, treatment of the cells with the two compounds caused prominent G 0 /G 1 phase arrest. Conclusion: Chamaejasmenin B and neochamaejasmin C are potential anti-proliferative agents in 8 human solid tumor cell lines in vitro via inducing cell cycle arrest, apoptosis and DNA damage.
Human hedgehog-interacting protein (HHIP), a negative regulator of hedgehog (HH) signaling pathway, has been reported to be dysregulated in many types of cancer, including gastric cancer. However, the inhibitory role of HHIP as well as the underlying molecular mechanism of HHIP regulation in gastric cancer haven’t been fully elucidated yet. In this study, we demonstrated that HHIP overexpression significantly suppressed the proliferation and invasion of AGS cells evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and transwell assays, respectively. Interestingly, methylation-specific polymerase chain reaction (MS-PCR, MSP) showed that HHIP overexpression dramatically decreased its de novo promoter methylation levels in AGS cells. Furthermore, HHIP expression was higher in adjacent non-cancerous tissue compared to matched gastric cancer tissue. High HHIP level was negatively correlated with metastasis (p = 0.035) but not local recurrence (p = 0.58). Taken together, our study suggested that HHIP can modulate gastric cancer progression and metastasis via regulation of its de novo promoter methylation levels in a feedback manner. Lower HHIP levels is positively associated with gastric cancer metastasis, which not only indicates HHIP could be served as a protective marker for gastric cancer, but also suggests restoring HHIP expression might be a potential therapeutic strategy for clinical treatment.
Abstract. The present study showed that the combination of dasatinib and combretastatin A-4 (CA-4) exhibited synergistic cytotoxicity in multiple types of cancer, including ovarian, hepatocellular, lung and prostate carcinoma. The enhanced apoptosis induced by dasatinib plus CA-4 was accompanied by a greater extent of mitochondrial depolarization, caspase-3 activation and PARP cleavage in HO-8910 cells. Furthermore, elevated expression of Mcl-1 led to a reduced apoptosis induced by dasatinib plus CA-4, highlighting that downregulated Mcl-1 was necessary for the potentiating effect of dasatinib to CA-4-triggered apoptosis. A clear increase in γ-H2AX expression was observed in the dasatinib + CA-4 group compared with the mono-treatment groups, indicating that dasatinib plus CA-4 may induce double-strand breaks (DSBs) in HO-8910 cells. Moreover, the increased anticancer efficacy of dasatinib combined with CA-4 was further validated in a human HO-8910 ovarian cancer xenograft model in nude mice. Our study is the first to show that the combination of dasatinib with CA-4 could be a novel and promising therapeutic approach for the treatment of cancer. IntroductionCombretastatin A-4 (CA-4), a natural product isolated from the bark of a south african tree combretum caffrum, is a highly effective antiangiogenic agent that causes vascular shutdown, leading to tumor death (1). CA-4 phosphate (CA-4P), a water soluble pro-drug of CA-4, is rapidly dephosphorylated to the active compound CA-4 and shows reversible binding kinetics to tubulin, leading to disruption of microtubular structures (2,3). Although CA-4P is being studied in clinical trials as a vascular disrupting agent, cardiovascular toxicity and neurotoxicity are dose limiting for CA-4P (4,5). These severe side-effects currently represent the main obstacles to broad clinical application of CA-4P (2). Thus, it is important to develop new antitumor combination therapy with lower concentrations of CA-4 and more specificity for tumor endothelial cells than normal endothelial cells to avoid cardiac toxicity from endothelial damage.Tyrosine kinase inhibitors (TKIs) are rapidly being integrated into the management of a variety of malignant diseases (6). Dasatinib, a novel orally bioactive TKI currently used to treat patients with hematologic and solid malignancies, correlated with a combined targeting of PDGFR-β and VEGFR/c-Src signaling pathways (7-9). The Src kinases have multiple substrates that lead to diverse biological effects in cancer cells, including changes in proliferation, motility, invasion, survival and angiogenesis (10). Dasatinib suppresses tumor angiogenesis, invasion, and metastasis by inhibiting Src expression (11). Cardiovascular and hematologic toxicity are dose limiting for dasatinib; thus, it is necessary to develop new anticancer combination therapy with lower concentrations of dasatinib to avoid these major side-effects (12). Dasatinib has shown synergistic anticancer activity in combination with chemotherapeutic agents including paclitaxel, ixabepil...
Bradykinin (BK) has been demonstrated to induce proliferation in several types of cell in ex vivo corneas. However, the mechanisms underlying the action of BK on corneal endothelial cells (CECs) remain largely unknown. The present study aimed to investigate the effect of BK on rabbit corneal endothelial cell (RCEC) proliferation, and assess the involvement of the zonula occludens-1(ZO-1)/ZO-1associated nucleic acid binding protein (ZONAB) pathway. Cell proliferation and cell cycle distribution was analyzed following treatment with BK (0.01, 0.1,1.0 or 10.0 µM) for the indicated time intervals (24, 48, 72 and 96 h), or following BK treatment combined with transfection of ZONAB-small interfering (si)RNA for 72 h. In addition, the expression of tight junction ZO-1, nuclear ZONAB, proliferating cell nuclear antigen(PCNA) and cyclin D1 were evaluated using western blotting or immunofluorescence. BK treatment was demonstrated to induce time- and concentration-dependent cell proliferation and cell cycle progression, along with the upregulation of tight junction ZO-1 and nuclear ZONAB, as well as PCNA and cyclin D1 protein expression. Furthermore, knockdown with ZONAB-siRNA inhibited cell proliferation, induced cell cycle arrest and downregulated PCNA and cyclin D1 protein expression. ZONAB knockdown therefore successfully reversed the increase in proliferation induced by BK treatment. Taken together, these results suggested that BK stimulated RCEC proliferation, potentially via the ZO-1/ZONAB pathway. The signaling paradigm disclosed in the present study potentially serves as an important therapeutic target for cornea regeneration and transplantation.
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