Bromodomain and extraterminal domain proteins, especially bromodomain-containing protein 4 (Brd4), have recently emerged as therapeutic targets for several cancers, although the role and mechanism of Brd4 in glioblastoma multiforme (GBM) are unclear. In this study, we aimed to explore the underlying mechanisms of the anti-tumor effects of Brd4 and the bromodomain inhibitor JQ1 on glioma stem cells (GSCs). In vitro, JQ1 and small interfering RNAs targeting Brd4 (siBrd4) inhibited the proliferation and self-renewal of GSCs. In vivo, JQ1 significantly inhibited the growth of xenograft GSCs tumors. The RNA-seq analysis revealed that the PI3K-AKT pathway played an important role in GBM. Vascular endothelial growth factor (VEGF) and VEGF receptor 2 phosphorylation was downregulated by exposure to JQ1 in GSCs, thereby reducing PI3K and AKT activity. In addition, treatment with JQ1 inhibited MMP expression, thereby inhibiting degradation of the extracellular matrix by MMP and angiogenesis in GBM tumors. Suppression of AKT phosphorylation inhibited the expression of the retinoblastoma/E2F1 complex, resulting in cell cycle arrest. In addition, treatment with siBrd4 or JQ1 induced apoptosis by activating AKT downstream target genes involved in apoptosis. In conclusion, these results suggest that Brd4 has great potential as a therapeutic target, and JQ1 has notable anti-tumor effects against GBM which may be mediated via the VEGF/PI3K/AKT signaling pathway.
The function of calcium efflux from the endoplasmic reticulum (ER) in cisplatin-induced apoptosis is not fully understood in cancer cells. The present study used western blot analysis, flow cytometry, immunofluorescence and 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay to investigate calcium signaling in human cervical cancer cells exposed to cisplatin. In the present study, treatment with cisplatin increased free Ca2+ levels in the cytoplasm and mitochondria of human cervical cancer HeLa cells, which further triggers the mitochondria-mediated and ER stress-associated apoptosis pathways. Notably, blocking calcium signaling using the calcium chelating agent bis-(o-aminophenoxy)ethane-N,N,N',N'-tetra-acetic acid acetoxymethyl ester inhibited cisplatin-induced apoptosis via downregulation of the calcium-dependent proteases, the calpains, and innate apoptosis proteins, such as caspsae-3, caspase-4 and C/EBP homologous protein (CHOP). In addition, use of the inositol triphosphate receptor inhibitor, 2-aminoethyl diphenylborinate, to inhibit calcium efflux from the ER resulted in similar effects. This data indicated that calcium efflux from the ER plays a significant role in cisplatin-induced apoptosis in human cervical cancer HeLa cells, which provides further mechanistic insights into the tumor cell-killing effect of cisplatin and potential therapeutic strategies to improve cisplatin chemotherapy.
Prostate carcinoma (PC) is one of the most common cancers for males. However, the molecular mechanisms of PC progression are still to be uncovered. MicroRNA (miRNA) has been shown to be associated with the initiation and progression of prostate cancer. Among the identified tumor-promoting miRNAs, miR-96 has been well established to contribute to PC by reducing FOXO1 expression. This study is aimed to study if miR-96 can promote the progression of PC through other pathways. Our data reinforced the finding that the level of miR-96 was higher in PC samples and cell lines than in non-cancerous tissues and normal prostate epithelial cells. In addition, serum miR-96 abundance was also found to be elevated in PC patients. Decreasing miR-96 expression was able to suppress the proliferation, clonogenicity, and invasion of PC cells. Overexpressing miR-96 led to increased proliferation and colony formation of normal prostate epithelial cells. miR-96 level was found to be inversely associated with the abundance of metastasis suppressor protein 1 (MTSS1) messenger RNA (mRNA), which has been proved to be a tumor suppressor for PC. Predictive analysis indicated that there was a potential miRNA response elements (MREs) located within 3'UTR of MTSS1 mRNA. The changes in miR-96 expression can affect the levels of MTSS1 both at mRNA and protein levels. miR-96 also suppressed the activity of luciferase reporter under the regulation of 3'UTR of MTSS1. Further studies showed that MTSS1 restoration accounted for the effect of miR-96 reduction on PC cells. The overexpression of a recombinant MTSS1 resistant against miRNA regulation was also demonstrated to abolish the transforming effect of miR-96 on prostate epithelial cells. Taken together, we found that miR-96 has a higher abundance in serum samples of PC patients than healthy controls, implying that it may be used as a prognostic marker. MTSS1 is a new authentic target of miR-96 in PC. The above findings suggested that targeting miR-96 may be a promising strategy for PC treatment.
Abstract. Choroidal melanoma is the most common primary intraocular tumor in adults. Cepharanthine (CEP), a natural alkaloid extracted from the roots of Stephania cepharantha Hayata, has been demonstrated to inhibit the proliferation of various cancer cells. However, its potential anticancer effect in choroidal melanoma has not been clarified yet. In the present study, it was identified that CEP may potently inhibit the proliferation of human choroidal melanoma cells, induce cell death and cell cycle arrest, and activate cellular apoptotic proteins, including Bcl-2-associated X protein, caspase and poly(ADP-ribose) polymerase. Results also revealed that CEP induced the cellular production of reactive oxygen species (ROS) and led to cytochrome c release, whereas concurrent treatment with N-acetyl-L-cysteine (a ROS scavenger) attenuated the situation. In addition, CEP was also revealed to activate c-Jun N-terminal kinase (JNK) 1 and 2, whereas inhibition of JNK1/2 partially abrogated the proliferation inhibitory effect of CEP, indicating that JNK1 and JNK2 were involved in CEP-triggered cellular apoptosis. In addition, the anticancer effects of CEP were also observed in a choroidal melanoma xenograft model. In summary, the results of the present study demonstrated that CEP is effective in suppressing human choroidal melanoma cell and tumor cell proliferation, and that CEP may therefore represent a potentially novel therapeutic agent for the treatment of choroidal melanoma. IntroductionChoroidal melanoma is the most common primary intraocular tumor in adults (1,2). The mean incidence of choroidal melanoma in the USA is ~6 novel cases/10 6 people every year (3). Currently, there are several treatment protocols for primary choroidal melanoma, including surgery, radiation therapy, thermotherapy and external beam proton therapy (4-7). The 5-year relative survival rate of choroidal melanoma is ~80% when the tumors are confined to the eyes (3,8). However, patients with choroidal melanoma have a high risk of developing metastasis (typically to the liver), which is usually fatal with a median survival time of 6-9 months subsequent to the detection of liver metastasis (3,8). Therefore, development of novel effective therapies for choroidal melanoma is required urgently.Cepharanthine(CEP; 6',12'-dimethoxy-2,2'-dimethyl-6,7-[methylenebis(oxy)]oxyacanthan) is a biscoclaurine alkaloid extracted from the roots of the plant Stephania cepharantha Hayata, which has been broadly used in Japan for chemoprevention and treatment of numerous diseases by virtue of its anti-inflammatory and immunomodulatory activities (9,10). CEP has been reported to exert antitumor effects in numerous cancers by inhibiting cancer cell proliferation (11), cell cycle progression (12), tumor invasion (13), generating reactive oxygen species (ROS) (11,14), inducing cell apoptosis (11,14,15), regulating cell survival signaling pathways (16,17) and increasing the competence of the host (18,19). It was also identified to potentiate the anticancer effects of oth...
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