Xiaoting Li

Curcumin Modulates miR-19/PTEN/AKT/p53 Axis to Suppress Bisphenol A-induced MCF-7 Breast Cancer Cell Proliferation

Breast cancer is the most common cancer in women. Bisphenol A (BPA), as a known endocrine disrupter, is closely related to the development of breast cancer. Curcumin has been clinically used in chemopreventation and treatment of cancer; however, it remains unknown whether microRNAs are involved in curcumin‐mediated protection from BPA‐associated promotive effects on breast cancer. In the present study, we showed that BPA exhibited estrogenic activity by increasing the proliferation of estrogen‐receptor‐positive MCF‐7 human breast cancer cells and triggering transition of the cells from G1 to S phase. Curcumin inhibited the proliferative effects of BPA on MCF‐7 cells. Meanwhile, BPA‐induced upregulation of oncogenic miR‐19a and miR‐19b, and the dysregulated expression of miR‐19‐related downstream proteins, including PTEN, p‐AKT, p‐MDM2, p53, and proliferating cell nuclear antigen, were reversed by curcumin. Furthermore, the important role of miR‐19 in BPA‐mediated MCF‐7 cell proliferation was also illustrated. These results suggest for the first time that curcumin modulates miR‐19/PTEN/AKT/p53 axis to exhibit its protective effects against BPA‐associated breast cancer promotion. Findings from this study could provide new insights into the molecular mechanisms by which BPA exerts its breast‐cancer‐promoting effect as well as its target intervention. Copyright

Curcumin Suppresses Lung Cancer Stem Cells via Inhibiting Wnt/β-catenin and Sonic Hedgehog Pathways

Cancer stem cells (CSCs) are highly implicated in the progression of human cancers. Thus, targeting CSCs may be a promising strategy for cancer therapy. Wnt/β‐catenin and Sonic Hedgehog pathways play an important regulatory role in maintaining CSC characteristics. Natural compounds, such as curcumin, possess chemopreventive properties. However, the interventional effect of curcumin on lung CSCs has not been clarified. In the present study, tumorsphere formation assay was used to enrich lung CSCs from A549 and H1299 cells. We showed that the levels of lung CSC markers (CD133, CD44, ALDHA1, Nanog and Oct4) and the number of CD133‐positive cells were significantly elevated in the sphere‐forming cells. We further illustrated that curcumin efficiently abolished lung CSC traits, as evidenced by reduced tumorsphere formation, reduced number of CD133‐positive cells, decreased expression levels of lung CSC markers, as well as proliferation inhibition and apoptosis induction. Moreover, we demonstrated that curcumin suppressed the activation of both Wnt/β‐catenin and Sonic Hedgehog pathways. Taken together, our data suggested that curcumin exhibited its interventional effect on lung CSCs via inhibition of Wnt/β‐catenin and Sonic Hedgehog pathways. These novel findings could provide new insights into the potential therapeutic application of curcumin in lung CSC elimination and cancer intervention. Copyright

Liquiritigenin induces mitochondria-mediated apoptosis via cytochrome c release and caspases activation in HeLa Cells.

It has been demonstrated that many flavonoids possess a potent and broad spectrum of antitumor activity. Liquiritigenin is a flavanone extracted from Glycyrrhizae. This study investigated the effects of liquiritigenin on cell viability and apoptosis induction in human cervical carcinoma (HeLa) cells. The results show that liquiritigenin significantly suppressed cell proliferation in a dose‐ and time‐dependent manner in HeLa cells. In addition, liquiritigenin promoted apoptosis in HeLa cells, evidenced by apoptotic morphological changes and Annexin‐V binding. The apoptosis induction with liquiritigenin is associated with the up‐regulation of p53 and Bax, along with down‐regulation of Bcl‐2 and survivin. Finally, examination of the mitochondrial pathway of apoptosis revealed that cytochrome c is released from mitochondria to cytosol, associated with the activation of caspase‐9 and ‐3, and the cleavage of poly (ADP‐ribose) polymerase (PARP). Overall, the results indicate that liquiritigenin induces apoptosis in part via the mitochondrial pathway, which is associated with p53 up‐regulation, release of cytochrome c and elevated activity of caspase‐9 and ‐3 in HeLa cells. Copyright

Anti-inflammatory Activity of Magnesium Isoglycyrrhizinate Through Inhibition of Phospholipase A2/Arachidonic Acid Pathway

Glycyrrhiza glabra (licorice) has been known to possess various pharmacological properties including anti-inflammatory, antioxidants, antiviral, and hepatoprotective activities. Magnesium isoglycyrrhizinate (MgIG), a magnesium salt of 18-α glycyrrhizic acid stereoisomer, is clinically used for the treatment of inflammatory liver diseases. However, the mechanism by which MgIG exerts its anti-inflammatory effects remains unknown. In the present study, we investigated the inhibitory potential of MgIG in phospholipase A2 (PLA2)/arachidonic acid (AA) pathway and release of the pathway-generated inflammatory lipid mediators in RAW264.7 macrophages. Results revealed that MgIG suppressed LPS-induced activation of PLA2 and production of AA metabolites such as prostaglandin E2 (PGE2), prostacyclin (PGI2), thromboxane 2 (TXB2), and leukotrienes (LTB4) in macrophages. Furthermore, LPS-induced AA-metabolizing enzymes including COX-2, COX-1, 5-LOX, TXB synthase, and PGI2 synthase were significantly inhibited by MgIG. Taken together, our data suggest that modulation of cyclooxygenase (COXs) and 5-lipoxygenase (LOX) pathways in AA metabolism could be a novel mechanism for the anti-inflammatory effects of MgIG.

Curcumin attenuates BPA-induced insulin resistance in HepG2 cells through suppression of JNK/p38 pathways

Bisphenol A (BPA) is an artificial environmental endocrine disrupting chemicals. Accumulating evidence indicates that exposure to BPA contributes to insulin resistance through diverse mechanism including inflammation and oxidative stress. Previous studies have suggested curcumin as a safe phytochemical which can improve obesity-related insulin resistance, inflammation and oxidative stress. The present study aimed to investigate the ability of curcumin to prevent BPA-induced insulin resistance in vitro and the underlying mechanism. Following the establishmet of in vitro insulin resistance via BPA treatment in human liver HepG2 cells, the protective effects of curcumin were determiend. We showed that treatment of HepG2 cells with 100nM BPA for 5days induced significantly decreased glucose consumption, impaired insulin signaling, elevation of pro-inflammatory cytokines and oxidative stress, and activation of signaling pathways; inhibition of JNK and p38 pathways, but not ERK nor NF-κB pathways, improved glucose consumption and insulin signaling in BPA-treated HepG2 cells. Moreover, we revealed that curcumin effectively attenuated the spectrum of effects of BPA-triggered insulin resistance, whereas pretreatment with JNK and p38 agonist anisomycin could significantly compensate the effects caused by curcumin. These data illustrated the role of JNK/p38 activation in BPA-induced insulin resistance and suggested curcumin as a promising candidate for the intervention of BPA-induced insulin resistance.

(−)-Epigallocatechin-3-Gallate Inhibits Colorectal Cancer Stem Cells by Suppressing Wnt/β-Catenin Pathway

The beneficial effects of tea consumption on cancer prevention have been generally reported, while (−)-Epigallocatechin-3-gallate (EGCG) is the major active component from green tea. Cancer stem cells (CSCs) play a crucial role in the process of cancer development. Targeting CSCs may be an effective way for cancer intervention. However, the effects of EGCG on colorectal CSCs and the underlying mechanisms remain unclear. Spheroid formation assay was used to enrich colorectal CSCs from colorectal cancer cell lines. Immunoblotting analysis and quantitative real-time polymerase chain reaction were used to measure the alterations of critical molecules expression. Immunofluorescence staining analysis was also used to determine the expression of CD133. We revealed that EGCG inhibited the spheroid formation capability of colorectal cancer cells as well as the expression of colorectal CSC markers, along with suppression of cell proliferation and induction of apoptosis. Moreover, we illustrated that EGCG downregulated the activation of Wnt/β-catenin pathway, while upregulation of Wnt/β-catenin diminished the inhibitory effects of EGCG on colorectal CSCs. Taken together, this study suggested that EGCG could be an effective natural compound targeting colorectal CSCs through suppression of Wnt/β-catenin pathway, and thus may be a promising agent for colorectal cancer intervention.

Curcumin Suppresses MAPK Pathways to Reverse Tobacco Smoke-induced Gastric Epithelial–Mesenchymal Transition in Mice

Tobacco smoke (TS) has been shown to cause gastric cancer. Epithelial–mesenchymal transition (EMT) is a crucial pathophysiological process in cancer development. Mitogen‐activated protein kinase (MAPK) pathways play central roles in tumorigenesis including EMT process. Curcumin is a promising chemopreventive agent for several types of cancers. In the present study, we investigated the effects of TS on MAPK pathway activation and EMT alterations in the stomach of mice, and the preventive effect of curcumin was further examined. Results showed that exposure of mice to TS for 12 weeks resulted in activation of extracellular regulated protein kinases 1 and 2 (ERK1/2), the Jun N‐terminal kinase (JNK), p38, and ERK5 MAPK pathways as well as activator protein 1 (AP‐1) proteins in stomach. TS reduced the mRNA and protein expression levels of the epithelial markers E‐cadherin and ZO‐1, while the mRNA and protein expression levels of the mesenchymal markers vimentin and N‐cadherin were increased. Treatment of curcumin effectively abrogated TS‐triggered gastric activation of ERK1/2 and JNK MAPK pathways, AP‐1 proteins, and EMT alterations. These results suggest for the first time the protective effects of curcumin in long‐term TS exposure‐induced gastric MAPK activation and EMT, thus providing new insights into the pathogenesis and chemoprevention of TS‐associated gastric cancer. Copyright

miR-19 targeting of GSK3β mediates sulforaphane suppression of lung cancer stem cells

Cancer stem cells (CSCs) play a central role in the development of cancer. The canonical Wnt/β-catenin pathway is critical for maintaining stemness of CSCs. Phytochemicals from dietary compounds possess anti-CSCs properties and have been characterized as promising therapeutic agents for the prevention and treatment of many cancers. To date, the involvement and function of miR-19, a key oncogenic miRNA, in regulating Wnt/β-catenin pathway and lung CSCs has not been defined. Meanwhile, the effect of sulforaphane (SFN) on lung CSCs also remains to be elucidated. Here, we reported that lung CSCs up-regulated miR-19a and miR-19b expression. Overexpression of miR-19a/19b enhanced the ability of tumorsphere formation, up-regulated the expression of lung CSCs markers, increased Wnt/β-catenin pathway activation and β-catenin/TCF transcriptional activity in lung CSCs. In contrary, down-regulation of miR-19 suppressed lung CSCs activity and Wnt/β-catenin activation. We further revealed that miR-19 activated Wnt/β-catenin pathway by directly targeting GSK3β, the key negative modulator of this pathway. Moreover, we showed that SFN exhibited inhibitory effect on lung CSCs through suppressing miR-19 and Wnt/β-catenin pathway. Taken together, these data illustrate the role of miR-19 in regulating lung CSCs traits and miR-19/GSK3β/β-catenin axis in SFN intervention of lung CSCs. Findings from this study could provide important new insights into the molecular mechanisms of lung CSCs regulation as well as its target intervention.

Diallyl Trisulfide inhibits breast cancer stem cells via suppression of Wnt/β-catenin pathway

Cancer stem cells (CSCs) play a central role in the development of breast cancer. The canonical Wnt/β‐catenin signal pathway is critical for maintaining CSCs characteristics. Diallyl trisulfide (DATS), a natural organosulfur compound from the garlic, exhibits effective antitumor properties. However, the role of DATS in regulating breast CSCs activity and the underlying molecular mechanisms remain obscure. In the present study, we reported that DATS efficiently inhibited the viability of breast CSCs as evidenced by reducing turmorspheres formation, decreasing the expression of breast CSCs markers (CD44, ALDH1A1, Nanog, and Oct4), as well as inhibiting proliferation and inducing apoptosis. Furthermore, we showed that DATS downregulated the activity of Wnt/β‐catenin pathway, while LiCl‐triggered Wnt/β‐catenin activation diminished DATS inhibition on breast CSCs. Taken together, our results illustrated that DATS suppressed breast CSCs through inhibiting Wnt/β‐catenin pathway activation. These novel findings could provide new insights into the molecular mechanisms of breast CSCs regulation as well as its target intervention and might provide new strategies for preventing and treating breast cancers.

Effects of Curcumin on Tobacco Smoke‐induced Hepatic MAPK Pathway Activation and Epithelial–Mesenchymal Transition In Vivo

Tobacco smoke is a major risk factor for hepatic cancer. Epithelial–mesenchymal transition (EMT) induced by tobacco smoke is crucially involved in the initiation and development of cancer. Mitogen‐activated protein kinase (MAPK) pathways play important roles in tobacco smoke‐associated carcinogenesis including EMT process. The chemopreventive effect of curcumin supplementation against cancers has been reported. In this study, we investigated the effects of tobacco smoke on MAPK pathway activation and EMT alterations, and then the preventive effect of curcumin was examined in the liver of BALB/c mice. Our results indicated that exposure of mice to tobacco smoke for 12 weeks led to activation of ERK1/2, JNK, p38 and ERK5 pathways as well as activator protein‐1 (AP‐1) proteins in liver tissue. Exposure of mice to tobacco smoke reduced the hepatic mRNA and protein expression of the epithelial markers, while the hepatic mRNA and protein levels of the mesenchymal markers were increased. Treatment of curcumin effectively attenuated tobacco smoke‐induced activation of ERK1/2 and JNK MAPK pathways, AP‐1 proteins and EMT alterations in the mice liver. Our data suggested the protective effect of curcumin in tobacco smoke‐triggered MAPK pathway activation and EMT in the liver of BALB/c mice, thus providing new insights into the chemoprevention of tobacco smoke‐associated hepatic cancer. Copyright