Monocarboxylate transporter 4 facilitates cell proliferation and migration and is associated with poor prognosis in oral squamous cell carcinoma patients.

Monocarboxylate transporter 4 (MCT4) is a cell membrane transporter of lactate. Recent studies have shown that MCT4 is over-expressed in various cancers; however, its role in cancer maintenance and aggressiveness has not been fully demonstrated. This study investigated the role of MCT4 in oral squamous cell carcinoma (OSCC), and found that it is highly expressed in OSCC patients by using immunohistochemistry. Moreover, this over-expression of MCT4 was closely associated with tumor size, TNM classification, lymphatic metastasis, distant metastasis and tumor recurrence, and also poor prognosis. To further study mechanisms of MCT4 in vitro, we used small-interfering RNA to silence its expression in OSCC cell lines. The results showed that knock-down of MCT4 decreased cell proliferation, migration, and invasion. The inhibition of proliferation was associated with down-regulation of p-AKT and p-ERK1/2, while decreased cell migration and invasion may be caused by down-regulation of integrin ß4-SRC-FAK and MEK-ERK signaling. Together, these findings provide new insight into the critical role of MCT4 in cell proliferation and metastasis in OSCC.

Inhibitory effect of Ginkgo biloba extract on fatty liver: regulation of carnitine palmitoyltransferase 1a and fatty acid metabolism.

OBJECTIVE: To investigate the potential effect of Ginkgo biloba extract (GBE) on the prevention and treatment of nonalcoholic fatty liver disease (NAFLD). METHODS: Male Wistar rats were divided into 4 groups (the control group, GBE group, high-fat diet [HFD] group and HFD + GBE group). The human hepatocellular carcinoma cell line (HepG2) was treated with GBE and its flavonoid ingredients. The fatty acid composition of the rat liver was analyzed with gas chromatography/time-of-flight mass spectrometry (GC/TOFMS). Triglyceride contents of both the rat liver and HepG2 cells were measured by enzymatic colorimetric method. The expressions of fatty acid metabolism-related genes were analyzed with real-time reverse transcription-polymerase chain reaction (RT-PCR). The protein expression and enzymatic activity were subsequently measured. RESULTS: In rat livers, GBE reduced the elevations of hepatic triglyceride contents caused by HFD and the increased hepatic fatty acids were differentially affected by GBE. Notably, the expression and total activity of the fatty acid ß-oxidation rate-limiting enzyme, carnitine palmitoyltransferase 1a (CPT1A), were also promoted with GBE ingestion. In HepG2 cells, GBE and its ingredients, quercetin, kaempferol and isorhamnetin, could decrease the cellular triglyceride content and upregulate the expression and total activity of CPT1A, respectively. CONCLUSIONS: The triglyceride-lowering effect of GBE on the HFD rat liver is closely associated with the increased expression and activity of CPT1A, and the flavonoid ingredients are the major contributors of GBE.

TRAPPC4-ERK2 interaction activates ERK1/2, modulates its nuclear localization and regulates proliferation and apoptosis of colorectal cancer cells.

The trafficking protein particle complex 4 (TRAPPC4) is implicated in vesicle-mediated transport, but its association with disease has rarely been reported. We explored its potential interaction with ERK2, part of the ERK1/2 complex in the Extracellular Signal-regulated Kinase/ Mitogen-activated Protein Kinase (ERK-MAPK) pathway, by a yeast two-hybrid screen and confirmed by co-immunoprecipitation (Co-IP) and glutathione S-transferase (GST) pull-down. Further investigation found that when TRAPPC4 was depleted, activated ERK1/2 specifically decreased in the nucleus, which was accompanied with cell growth suppression and apoptosis in colorectal cancer (CRC) cells. Overexpression of TRAPPC4 promoted cell viability and caused activated ERK1/2 to increase overall, but especially in the nucleus. TRAPPC4 was expressed more highly in the nucleus of CRC cells than in normal colonic epithelium or adenoma which corresponded with nuclear staining of pERK1/2. We demonstrate here that TRAPPC4 may regulate cell proliferation and apoptosis in CRC by interaction with ERK2 and subsequently phosphorylating ERK1/2 as well as modulating the subcellular location of pERK1/2 to activate the relevant signaling pathway.

Molecular mechanisms underlying the cholesterol-lowering effect of Ginkgo biloba extract in hepatocytes: a comparative study with lovastatin.

AIM: To explore the molecular mechanisms underlying the cholesterol-lowering effect of a Ginkgo biloba extract (GBE). METHODS: Enzyme activity, cholesterol flux and changes in gene expression levels were assessed in cultured hepatocytes treated with GBE or lovastatin. RESULTS: GBE decreased the total cholesterol content in cultured hepatocytes and inhibited the activity of HMG-CoA reductase, as determined by an in vitro enzyme activity assay. In addition, GBE decreased cholesterol influx, whereas lovastatin increased cholesterol influx. GBE treatment induced significant increases in the expression of cholesterogenic genes and genes involved in cholesterol metabolism, such as SREBF2, as determined by cDNA microarray and real-time RT-PCR. Furthermore, INSIG2, LDLR, LRP1, and LRP10 were differentially regulated by GBE and lovastatin. The data imply that the two compounds modulate cholesterol metabolism through distinct mechanisms. CONCLUSION: By using a gene expression profiling approach, we were able to broaden the understanding of the molecular mechanisms by which GBE lowers cellular cholesterol levels. Specifically, we demonstrated that GBE exhibited dual effects on the cellular cholesterol pool by modulating both HMG-CoA reductase activity and inhibiting cholesterol influx.