4EBP1 senses extracellular glucose deprivation and initiates cell death signaling in lung cancer.

Nutrient-limiting conditions are common during cancer development. The coordination of cellular glucose levels and cell survival is a fundamental question in cell biology and has not been completely understood. 4EBP1 is known as a translational repressor to regulate cell proliferation and survival by controlling translation initiation, however, whether 4EBP1 could participate in tumor survival by other mechanism except for translational repression function, especially under glucose starvation conditions remains unknown. Here, we found that protein levels of 4EBP1 was up-regulated in the central region of the tumor which always suffered nutrient deprivation compared with the peripheral region. We further discovered that 4EBP1 was dephosphorylated by PTPMT1 under glucose starvation conditions, which prevented 4EBP1 from being targeted for ubiquitin-mediated proteasomal degradation by HERC5. After that, 4EBP1 translocated to cytoplasm and interacted with STAT3 by competing with JAK and ERK, leading to the inactivation of STAT3 in the cytoplasm, resulting in apoptosis under glucose withdrawal conditions. Moreover, 4EBP1 knockdown increased the tumor volume and weight in xenograft models by inhibiting apoptosis in the central region of tumor. These findings highlight a novel mechanism for 4EBP1 as a new cellular glucose sensor in regulating cancer cell death under glucose deprivation conditions, which was different from its classical function as a translational repressor.

Application of Deep Learning-Based Integrated Trial-Error + Science, Technology, Reading/Writing, Engineer, Arts, Mathematics Teaching Mode in College Entrepreneurship Education.

The purpose is to achieve a high-quality teaching effect in quality education using the new teaching concept. Firstly, the Deep Learning (DL) theory is introduced to improve the trial-error teaching method, then the trial-error teaching is combined with STREAM education. Afterward, the conical section hyperbola teaching in college entrepreneurship education is specifically studied under experimental analysis using the proposed DL-based integrated trail-error + STREAM teaching methods. The experimental results read: student's average veracity on the multiple-choice question is 93.4% and 90.1% for the experimental group and control group, respectively; student's average veracity on short-answer questions is 92.3% and 90.3% for the experimental group and control group, respectively. The results show that the application of DL to the trial-error teaching method can cultivate students' in-depth analysis and logical thinking ability for mathematical problems. Meanwhile, the DL-based integrated trial-error + STREAM teaching methods stimulate students' initiative to learn more difficult knowledge, establish integral knowledge systems, and more comprehensively and deeply understand the teaching content. As a result, students' scientific literacy and humanistic literacy are both improved. Therefore, the proposed DL-based integrated trial-error + STREAM teaching method in college entrepreneurship education has a guiding significance for other disciplines and provides ideas for the expansion and development of STREAM teaching in the future.

E3 ubiquitin ligase TRIM7 negatively regulates NF-kappa B signaling pathway by degrading p65 in lung cancer.

The gene trim7 encodes at least four isoforms Glycogenin-interacting protein 1 (GNIP1), GNIP2, GNIP3 and Tripartite motif containing 7 (TRIM7). GNIP1, the longest isoform, has been reported acting as an oncogene. However, it is very interesting that TRIM7, the shortest isoform, only 15 amino acids different from GNIP1 in C-terminal, acts in a completely different way from that of GNIP1 in our present study. TRIM7 expression was decreased in tumor compared with adjacent normal tissues, and the level of TRIM7 was negatively correlated with clinical stage of 94 patients with lung cancer. In vitro, TRIM7 dramatically inhibited the proliferation and migration of tumor cells, and promoted cell apoptosis. Further study showed that TRIM7 interacted with p65 via its C-terminal which is different from GNIP1. The interaction between TRIM7 and p65 promoted the ubiquitination of p65 and finally accelerated the degradation of p65 via 26S proteasome. In vivo, the tumor volume and weight were decreased by TRIM7 stable expression. Meanwhile, Ki67 was down-regulated, thyroid transcription factor 1 (TTF-1) and Caspase 3 were up-regulated in TRIM7 overexpression group in xenograft model. It is very impressive that TRIM7t (a truncated TRIM7 without C-terminal sequence that different with GNIP1) had little effect on the tumor growth in vivo. These findings highlight a curious mechanism for negative regulation of NF-kappa B signaling pathway by TRIM7 and demonstrate that TRIM7 would be a potential therapeutic target for lung cancer.

Effects of air pollution control measures on air quality improvement in Guangzhou, China.

The ambient air quality of Guangzhou in 2016 has significantly improved since Guangzhou and its surrounding cities implemented a series of air pollution control measures from 2014 to 2016. This study not only estimated the effects of meteorology and emission control measures on air quality improvement in Guangzhou but also assessed the contributions of emissions reduction from various sources through the combination of observation data and simulation results from Weather Research and Forecasting - Community Multiscale Air Quality (WRF-CMAQ) modeling system. Results showed that the favorable meteorological conditions in 2016 alleviated the air pollution. Compared to change in meteorology, implementing emission control measures in Guangzhou and surrounding cities was more beneficial for air quality improvement, and it could reduce the concentrations of SO2, NO2, PM2.5, PM10, and O3 by 9.7 µg m-3 (48.4%), 9.2 µg m-3 (17.7%), 7.7 µg m-3 (14.6%), 9.7 µg m-3 (13.4%), and 12.0 µg m-3 (7.7%), respectively. Furthermore, emission control measures that implemented in Guangzhou contributed most to the concentration reduction of SO2, NO2, PM2.5, and PM10 (46.0% for SO2, 15.2% for NO2, 9.4% for PM2.5, and 9.1% for PM10), and it increased O3 concentration by 2.4%. With respect to the individual contributions of source emissions reduction, power sector emissions reduction showed the greatest contribution in reducing the concentrations of SO2, NO2, PM2.5, and PM10 due to the implementation of Ultra-Clean control technology. As for O3 mitigation, VOCs product-related source emissions reduction was most effective, and followed by transportation source emissions reduction, while the reductions of power sector, industrial boiler, and industrial process source might not be as effective. Our findings provide scientific advice for the Guangzhou government to formulate air pollution prevention and control policies in the future.

A novel function of anaphase promoting complex subunit 10 in tumor progression in non-small cell lung cancer.

The anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase, is responsible for the transition from metaphase to anaphase and the exit from mitosis. The anaphase promoting complex subunit 10 (APC10), a subunit of the APC/C, executes a vital function in substrate recognition. However, no research has reported the connection between APC10 and cancer until now. In this study, we uncovered a novel, unprecedented role of APC10 in tumor progression, which is independent of APC/C. First, aberrant increase of APC10 expression was validated in non-small cell lung cancer (NSCLC) cells and tissues, and the absence of APC10 repressed cell proliferation and migration. Of great interest, we found that APC10 inhibition induced cell cycle arrest at the G0/G1 phase and reduced the expression of the APC/C substrate, Cyclin B1; this finding is different from the conventional concept of the accumulation of Cyclin B1 and cell cycle arrest in metaphase. Further, APC10 was found to interact with glutaminase C (GAC), and the inhibition of APC10 weakened glutamine metabolism and induced excessive autophagy. Taken together, these findings identify a novel function of APC10 in the regulation of NSCLC tumorigenesis and point to the possibility of APC10 as a new target for cancer therapy.

Shikonin exerts antitumor activity by causing mitochondrial dysfunction in hepatocellular carcinoma through PKM2-AMPK-PGC1α signaling pathway.

Shikonin, a naphthoquinone derivative isolated from the root of Lithospermum erythrorhizon, exhibits broad-spectrum antitumor activity via different molecular mechanisms. In this study, we investigated the effect of shikonin on mitochondrial dysfunction in hepatocellular carcinoma (HCC). Our results showed that shikonin inhibited the proliferation, migration, and invasiveness of HCCLM3 cells, and promoted cell apoptosis in a dose-dependent manner. More importantly, shikonin affected mitochondrial function by disrupting mitochondrial membrane potential and oxidative stress (OS) status. Furthermore, shikonin decreased the oxygen consumption rate of HCCLM3 cells, as well as the levels of ATP and metabolites involved in the tricarboxylic acid cycle (TCA cycle). We also investigated the molecular mechanisms underlying the regulation of mitochondrial function by shikonin as an inhibitor of PKM2. Shikonin decreased the expression of PKM2 in the mitochondria and affected other metabolic pathways (AMPK and PGC1α pathways), which aggravated the oxidative stress and nutrient deficiency. Our results indicate a novel role of shikonin in triggering mitochondria dysfunction via the PKM2-AMPK-PGC1α signaling pathway and provide a promising therapeutic approach for the treatment of HCC.

Fatty acid binding protein 4 promotes epithelial-mesenchymal transition in cervical squamous cell carcinoma through AKT/GSK3ß/Snail signaling pathway.

Fatty acid binding protein 4 (FABP4) is a member of the fatty acid binding protein family which involved in a variety of biological cellular processes, including tumorigenesis. However, the role of this key adipokine in cervical cancer is still unclear. In this study, we explored the function of FABP4 in cervical cancer and the underlying molecular mechanisms. FABP4 was specifically elevated in tissue samples from patients with cervical squamous cell carcinoma (CSCC) but not with cervical adenocarcinoma, and the level of FABP4 was correlated with E-cadherin and Vimentin expression. In vitro, exogenous FABP4 promoted the migration and invasion of CSCC cells in a dose-dependent manner, and reorganized the actin cytoskeletons in F-Actin staining and TGF-ß induced EMT assays. Importantly, the AKT/GSK3ß/Snail pathway appears to be involved in FABP4-induced EMT in CSCC cells. In conclusion, our research demonstrated elevated FABP4 promoted EMT via the activation of AKT/GSK3ß/Snail pathway in CSCC.

GRHL2 suppresses tumor metastasis via regulation of transcriptional activity of RhoG in non-small cell lung cancer.

The transcription factor, Grainyhead-like 2 (GRHL2), is involved in wound healing, epidermal integrity, and epithelial-to-mesenchymal transition (EMT) in various biological processes; however, the biological function of GRHL2 in non-small cell lung cancer (NSCLC) is unknown. In the current study, we investigated the effect of GRHL2 on cell growth and migration in NSCLC cell lines and clinical tissues. Immunohistochemical analysis of clinical NSCLC specimens revealed that patients with high GRHL2 expression were associated with poor prognosis compared to patients with low GRHL2 expression. GRHL2 overexpression promoted cell growth and colony formation, and simultaneously suppressed cell migration in NSCLC cells. Furthermore, GRHL2 decreased the transcriptional activity of RhoG by directly binding to the RhoG promoter region. These findings confirm that GRHL2 plays an important role in regulating cell proliferation and migration in NSCLC.

Dihydromyricetin ameliorates oleic acid-induced lipid accumulation in L02 and HepG2 cells by inhibiting lipogenesis and oxidative stress.

AIMS: Dihydromyricetin (DMY), a flavonoid component isolated from Ampelopsis grossedentata, was recently reported to ameliorate nonalcoholic fatty liver disease (NAFLD) in patients. However, the underlying mechanisms of this action remain unknown. Here, we evaluate the effect of DMY on an in vitro model of NAFLD and investigate the signal transduction pathways underlying DMY treatment. MAIN METHODS: Oleic acid (OA) induced hepatic steatosis was established in L02 and HepG2 cells as in vitro model of NAFLD. Cell apoptosis, lipid accumulation and oxide stress were evaluated by flow cytometry, oil red O staining, and cellular biochemical assays, respectively. Signaling pathways involved in lipid metabolism including PPARγ, AMPK, and AKT were investigated by Western blot and RT-qPCR. KEY FINDINGS: DMY protected cells against apoptosis and lipid accumulation induced by oleic acid. DMY decreased the levels of cellular triglycerides (TG), cholesterol (TC) and malondialdehyde (MDA), while at the same time increasing the level of superoxide dismutase (SOD). DMY suppressed the expression of PPARγ and the phosphorylation of AKT, and promoted the phosphorylation of AMPK. SIGNIFICANCE: Our study suggests that DMY ameliorates OA-induced hepatic steatosis by inhibiting cell apoptosis, lipid accumulation and oxide stress. Furthermore, the effect of DMY is likely associated with its role in the regulating of PPARγ, AMPK and AKT signaling pathways.

Inhibition of mitochondrial glutaminase activity reverses acquired erlotinib resistance in non-small cell lung cancer.

The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib has been approved based on the clinical benefit in non-small cell lung cancer (NSCLC) patients over the past decade. Unfortunately, cancer cells become resistant to this agent via various mechanisms, and this limits the improvement in patient outcomes. Thus, it is urgent to develop novel agents to overcome erlotinib resistance. Here, we propose a novel strategy to overcome acquired erlotinib resistance in NSCLC by inhibiting glutaminase activity. Compound 968, an inhibitor of the glutaminase C (GAC), when combined with erlotinib potently inhibited the cell proliferation of erlotinib-resistant NSCLC cells HCC827ER and NCI-H1975. The combination of compound 968 and erlotinib not only decreased GAC and EGFR protein expression but also inhibited GAC activity in HCC827ER cells. The growth of erlotinib-resistant cells was glutamine-dependent as proved by GAC gene knocked down and rescue experiment. More importantly, compound 968 combined with erlotinib down-regulated the glutamine and glycolysis metabolism in erlotinib-resistant cells. Taken together, our study provides a valuable approach to overcome acquired erlotinib resistance by blocking glutamine metabolism and suggests that combination of EGFR-TKI and GAC inhibitor maybe a potential treatment strategy for acquired erlotinib-resistant NSCLC.