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[en] Pancreatic cancer is the fourth leading cause of cancer death. Gemcitabine is widely used as a chemotherapeutic agent for the treatment of pancreatic cancer, but the prognosis is still poor. Berberine, an isoquinoline alkaloid extracted from a variety of natural herbs, possesses a variety of pharmacological properties including anticancer effects. In this study, we investigated the anticancer effects of berberine and compared its use with that of gemcitabine in the pancreatic cancer cell lines PANC-1 and MIA-PaCa2. Berberine inhibited cell growth in a dose-dependent manner by inducing cell cycle arrest and apoptosis. After berberine treatment, the G1 phase of PANC-1 cells increased by 10% compared to control cells, and the G1 phase of MIA-PaCa2 cells was increased by 2%. Whereas gemcitabine exerts antiproliferation effects through S-phase arrest, our results showed that berberine inhibited proliferation by inducing G1-phase arrest. Berberine-induced apoptosis of PANC-1 and MIA-PaCa2 cells increased by 7 and 2% compared to control cells, respectively. Notably, berberine had a greater apoptotic effect in PANC-1 cells than gemcitabine. Upon treatment of PANC-1 and MIA-PaCa2 with berberine at a half-maximal inhibitory concentration (IC_5_0), apoptosis was induced by a mechanism that involved the production of reactive oxygen species (ROS) rather than caspase 3/7 activation. Our findings showed that berberine had anti-cancer effects and may be an effective drug for pancreatic cancer chemotherapy
[en] In recent years, long non-coding RNAs (lncRNAs) have gained significant attention as a novel class of gene regulators. Although a small number of lncRNAs have been shown to regulate gene expression through diverse mechanisms including transcriptional regulation, mRNA splicing and translation, the physiological function and mechanism of action of the vast majority are not known. Profiling studies in cell lines and tumor samples have suggested a potential role of lncRNAs in cancer. Indeed, distinct lncRNAs have been shown to be embedded in the p53 and Rb networks, two of the major tumor suppressor pathways that control cell cycle progression and survival. Given the fact that inactivation of Rb and p53 is a hallmark of human cancer, in this review we discuss recent evidence on the function of lncRNAs in the Rb and p53 signaling pathways
[en] MicroRNAs (miRNAs) are small, noncoding RNAs which regulate cell differentiation, proliferation, development, cell cycle, and apoptosis. Expression profiling of miRNAs has been performed and the data show that some miRNAs are upregulated or downregulated in cancer. Several studies suggest that the expression profiles of miRNAs are associated with clinical outcomes. However, the set of miRNAs with altered expressing differs depending on the type of cancer, suggesting that it is important to understand which miRNAs are related to which cancers. Therefore, this review aimed to discuss potentially crucial miRNAs in head and neck squamous cell carcinoma (HNSCC) and oral squamous cell carcinoma (OSCC)
[en] Effects of Noopept (N-phenylacetyl-L-prolylglycine ethyl ester) on the relative level of proliferation marker Ki-67 and cell cycle parameters were studied in HEK293 and SH-SY5Y cell lines. The previously established multifactorial mechanism of action of the drug includes enhancement of neurotrophin NGF and BDNF expression and increase in HIF-1 activity. The possible mitogenic action of Noopept was estimated by its effect on cell proliferation. Noopept did not affect cell distribution over G1, S, G2 cell cycle phases and the relative level of proliferation marker Ki-67 in the cell lines under study. These data suggest that Noopept does not stimulate cell growth.
[en] Rottlerin has been reported to exert its anti-tumor activity in various types of human cancers. However, the underlying molecular mechanism has not been fully elucidated. In the current study, we explored whether rottlerin exhibits its tumor suppressive function in hepatocellular carcinoma cells. Our MTT assay results showed that rottlerin inhibited cell growth in hepatocellular carcinoma cells. Moreover, we found that rottlerin induced cell apoptosis and caused cell cycle arrest at G1 phase. Furthermore, our wound healing assay result demonstrated that rottlerin retarded cell migration in hepatocellular carcinoma cells. Additionally, rottlerin suppressed cell migration and invasion. Notably, we found that rottlerin upregulated DDX3 expression and subsequently downregulated Cyclin D1 expression and increased p21 level. Importantly, down-regulation of DDX3 abrogated the rottlerin-mediated tumor suppressive function, whereas overexpression of DDX3 promoted the anti-tumor activity of rottlerin. Our study suggests that rottlerin exhibits its anti-cancer activity partly due to upregulation of DDX3 in hepatocellular carcinoma cells.
[en] The activation of caspase proteases and the targeting of protein substrates act as key steps in the engagement and conduct of apoptosis/programmed cell death. However, the discovery of caspase involvement in diverse non-apoptotic cellular functions strongly suggests that these proteins may have evolved from a core behavior unrelated to the induction of cell death. The presence of similar proteases, termed metacaspases, in single cell organisms supports the contention that such proteins may have co-evolved or derived from a critical non-death function. Indeed, the benefit(s) for single cell life forms to retain proteins solely dedicated to self destruction would be countered by a strong selection pressure to curb or eliminate such processes. Examination of metacaspase biology provides evidence that these ancient protease forerunners of the caspase family also retain versatility in function, i.e., death and non-death cell functions. Here, we provide a critical review that highlights the non-death roles of metacaspases that have been described thus far, and the impact that these observations have for our understanding of the evolution and cellular utility of this protease family.
[en] CUL4A; an E3 ubiquitin ligase is involved in the degradation of negative regulators of cell cycle such as p21, p27, p53, etc., through polyubiquitination-mediated protein degradation. The functional role(s) of CUL4A proteins on their targets are well characterized; however, the transcriptional regulation of CUL4A, particularly at its promoter level is not yet studied. Therefore, in this study, using computational tools, we found cAMP responsive elements (CRE) at the locations of − 926 and − 764 with respect to transcription state site + 1 of CUL4A promoter. Hence, we investigated the role of CREB on the regulation of CUL4A transcription. Our chromatin immunoprecipitation (ChIP) data clearly showed increased levels of promoter occupancy of both CREB and pCREB on both CREs of CUL4A promoter. As expected, the expression of CUL4A increases and decreases upon the overexpression of and knocking down of CREB, respectively. Moreover, the inhibition of ERK pathway by U0126 not only reduces the CREB activation but also the CUL4A levels suggesting that CREB is the upstream activator of CUL4A transcription. The reduction of CUL4A levels upon the knocking down of CREB or by U0126 treatment increases the protein levels of CUL4A substrates such as p21 and p27. It is reported that CUL4A activates the ERK1/2 transcription and ERK1/2 pathway activates the CREB by phosphorylation. Based on our data and earlier findings, we report that CREB regulates the CUL4A levels positively which in turn activates the CREB through ERK1/2 pathway in the form of auto-regulatory looped mechanism.This suggests that CUL4A might be involved in proliferation of cancer cells by regulating the ERK1/2 and CREB signaling.
[en] Highlights: • We first confirmed that FOXP4-AS1 is overexpressed in OS, and is the independent risk factor in OS prognosis. • We further clarified that Upregulated FOXP4-AS1 promotes the proliferation, migration and cell cycle, but inhibits apoptosis of OS cells. • Finally, we demonstrated that FOXP4-AS1 participates in the development and progression of OS by downregulating LATS1. Osteosarcoma (OS) is the most common malignant bone tumor in children and adolescents. LncRNA has been confirmed to participate in a variety of cancers. The purpose of this study was to explore the effect of FOXP4-AS1 on the development of osteosarcoma (OS) and its underlying mechanism. FOXP4-AS1 expressions in 60 OS tissues and paracancerous tissues were detected by qRT-PCR (quantitative real-time polymerase chain reaction). We confirmed that FOXP4-AS1 was overexpressed in OS tissues than that of paracancerous tissues. The disease-free survival and overall survival of OS patients were not correlated with age, gender and tumor location, but remarkably correlated with FOXP4-AS1 expression, tumor size and lung metastasis. For in vitro experiments, MG63 cells expressed a higher expression of FOXP4-AS1, whereas U2OS cells expressed a lower expression, which were selected for the following studies. Overexpressed FOXP4-AS1 led to enhanced proliferation, migration and invasion, shortened G0/G1 phase, as well as inhibited cell cycle. Knockdown of FOXP4-AS1 in MG63 cells obtained the opposite results. Furthermore, RIP assay indicated that FOXP4-AS1 could inhibit LATS1 expression by binding to LSD1 and EZH2, so as to participate in OS development. In conclusion, these results revealed that FOXP4-AS1 is overexpressed in OS, and is the independent risk factor in OS prognosis. Upregulated FOXP4-AS1 promotes the proliferation, migration and cell cycle, but inhibits apoptosis of OS cells. Furthermore, FOXP4-AS1 participates in the development and progression of OS by downregulating LATS1 via binding to LSD1 and EZH2.
[en] Because epigenetic alterations are believed to be involved in the repression of tumor suppressor genes and promotion of tumorigenesis in choriocarcinomas, novel compounds endowed with a histone deacetylase (HDAC) inhibitory activity are an attractive therapeutic approach. HDAC inhibitors (HDACIs) were able to mediate inhibition of cell growth, cell cycle arrest, apoptosis, and the expression of genes related to the malignant phenotype in choriocarcinoma cell lines. In this review, we discuss the biologic and therapeutic effects of HDACIs in treating choriocarcinoma, with a special focus on preclinical studies
[en] The proper organization of microtubules is essential for many cellular functions. Microtubule organization and reorganization are highly regulated during the cell cycle, but the underlying mechanisms remain elusive. Here we characterized unusual interphase microtubule organization in fission yeast nuclear export mutant crm1-124. The mutant cells have an intranuclear microtubule bundle during interphase that pushes the nuclear envelope to assume a protruding morphology. We showed that the formation of this protruding microtubule bundle requires the nuclear accumulation of two microtubule-associated proteins (MAPs), Alp14/TOG and Mal3/EB1. Interestingly, the forced accumulation of Alp14 in the nucleus of wild type cells is sufficient to form the intranuclear microtubule bundle. Furthermore, the frequency of the intranuclear microtubule formation by Alp14 accumulated in the nucleus is prominently increased by a reduction in the nucleation activity of interphase cytoplasmic microtubules. We propose that properly regulated nucleocytoplasmic transport and maintained activity of cytoplasmic microtubule nucleation during interphase are important for the proper organization of interphase cytoplasmic microtubules.