β-elemene, a compound derived from Rhizoma zedoariae, is a promising new plant-derived drug with broad-spectrum anticancer activity. However, the underlying mechanism by which this agent inhibits human lung cancer cell growth has not been well elucidated. In this study, we showed that β-elemene inhibits human non-small cell lung carcinoma (NSCLC) cell growth, and increased phosphorylation of ERK1/2, Akt and AMPKα. Moreover, β-elemene inhibited expression of DNA methyltransferase 1 (DNMT1), which was not observed in the presence of the specific inhibitors of ERK (PD98059) or AMPK (compound C). Overexpression of DNMT1 reversed the effect of β-elemene on cell growth. Interestingly, metformin not only reversed the effect of β-elemene on phosphorylation of Akt but also strengthened the β-elemene-reduced DNMT1. In addition, β-elemene suppressed Sp1 protein expression, which was eliminated by either ERK1/2 or AMPK inhibitor. Conversely, overexpression of Sp1 antagonized the effect of β-elemene on DNMT1 protein expression and cell growth. Taken together, our results show that β-elemene inhibits NSCLC cell growth viaERK1/2- and AMPKα-mediated inhibition of transcription factor Sp1, followed by reduction in DNMT1 protein expression. Metformin augments the effect of β-elemene by blockade of Akt signalling and additively inhibition of DNMT1 protein expression. The reciprocal ERK1/2 and AMPKα signalling pathways contribute to the overall responses of β-elemene. This study reveals a potential novel mechanism by which β-elemene inhibits growth of NSCLC cells.

microRNAs (miRNAs) and DNA methylation are the 2 epigenetic modifications that have emerged in recent years as the most critical players in the regulation of gene expression. Compelling evidence has indicated the roles of miRNAs and DNA methylation in modulating cellular transformation and tumorigenesis. miRNAs act as negative regulators of gene expression and are involved in the regulation of both physiologic conditions and during diseases, such as cancer, inflammatory diseases, and psychiatric disorders, among others. Meanwhile, aberrant DNA methylation manifests in both global genome changes and in localized gene promoter changes, which influences the transcription of cancer genes. In this review, we described the mutual regulation of miRNAs and DNA methylation in human cancers. miRNAs regulate DNA methylation by targeting DNA methyltransferases or methylation-related proteins. On the other hand, both hyper-and hypo-methylation of miRNAs occur frequently in human cancers and represent a new level of complexity in gene regulation. Therefore, understanding the mechanisms underlying the mutual regulation of miRNAs and DNA methylation may provide helpful insights in the development of efficient therapeutic approaches.

BackgroundBerberine (BBR), a component from traditional Chinese medicine, has been shown to possess anti-tumor activity against a wide spectrum of cancer cells including human lung cancer, but the detailed mechanism underlining this has not been well elucidated.MethodsIn this study, the effect of berberine on cell growth and apoptosis were assessed by MTT, flow cytometry and Hoechst 33258 staining assays. The phosphorylation of p38 MAPK and ERK1/2, and expressions of p38 MAPK isoforms α and β, total ERK1/2, p53, FOXO3a and p21 protein were evaluated by Western Blot analysis. Silencing of p38 MAPK isoform α and β, p53, FOXO3a and p21 were performed by siRNA methods. Exogenous expression of FOXO3a was carried out by electroporated transfection assays.ResultsWe showed that BBR significantly inhibited growth and induced cell cycle arrest of non small cell lung cancer (NSCLC) cells in the G0/G1 phase in a dose-dependent manner. Furthermore, we found that BBR increased phosphorylation of p38 MAPK and ERK1/2 in a time-dependent and induced protein expression of tumor suppressor p53 and transcription factor FOXO3a in a dose-dependent fashion. The specific inhibitor of p38 MAPK (SB203580), and silencing of p38α MAPK by small interfering RNAs (siRNAs), but not ERK1/2 inhibitor (PD98059) blocked the stimulatory effects of BBR on protein expression of p53 and FOXO3a. Interestingly, inhibition of p53 using one specific inhibitor (Pifithrin-α) and silencing of p53 using siRNAs overcome the inhibitory effect of BBR on cell growth. Silencing of FOXO3a appeared to attenuate the effect of BBR on p53 expression, cell proliferation and apoptosis. Furthermore, BBR induces the protein expression of cell cycle inhibitor p21 (CIP1/WAF1), which was not observed in cells silencing of p53 or FOXO3α gene. Intriguingly, exogenous expression of FOXO3a enhanced the expression of p21 (CIP1/WAF1) and strengthened BBR-induced apoptosis.ConclusionOur results show that BBR inhibits proliferation and induces apoptosis of NSCLC cells through activation of p38α MAPK signaling pathway, followed by induction of the protein expression of p53 and FOXO3a. The latter contribute to the BBR-increased p21 (CIP1/WAF1) protein expression. The exogenous FOXO3a, interaction and mutually exclusive events of p53 and FOXO3a augment the overall response of BBR.

Complementary and alternative medicine (CAM) plays a critical role in treating cancer patients. Traditional Chinese Medicine (TCM) is the main component of CAM. TCM, especially Chinese Herbal Medicine (CHM), has been increasingly used in China, some other Asian countries and European countries. It has been proven to enhance the efficacy of chemotherapy, radiotherapy, targeted-therapy, and immunotherapy. It lessens the damage caused by these therapies. CHM functions on cancer by inhibiting tumor progression and improving an organism’s immune system. Increasing evidence has shown that many CHM exert favorable effects on the immune regulation. We will summarize the role of CHM on patient’s immune system when treating cancer patients. Our evidence reveals that single herbs, including their extracts, compound formulations, and preparations, will provide current advances on CHM study, especially from the perspective of immune regulation and novel insights for CHM application in clinic. The main herbs used to treat cancer patients are health-strengthening (Fu-Zheng) herbs and pathogen eliminating (Qu-Xie) herbs. The key mechanism is regulating the immune system of cancer patients. Firstly, health-strengthening herbs are mainly functioned as immune regulatory effectors on cancer. Secondly, some of the compound formulations mainly strengthen the health of patients by regulating the immune system of cancer patients. Lastly, some Chinese medicine preparations are widely used to treat cancer for their properties of spiriting vital energy and anti-cancer effects, mainly by improving immunity. CHM plays a positive role in regulating patients’ immune system, which helps cancer patients to fight against cancer itself and finally improves patients’ life quality.