Dexmedetomidine Associated Lung Cancer Proliferation and Tumor Growth is Prevented by β-Caryophyllene: Role of AMPK Activation and PGC-1α/TFAM Over Expression

Background: Dexmedetomidine has been reported to induce anti-apoptotic effects and metastatic progression in lung cancer. In the current investigation, the effect of β-Caryophyllene on dexmedetomidine induced cell proliferation and apoptosis of lung cancer cells and tumor growth in mice was studied. Methods: A549 cell line was cultured with either dexmedetomidine alone or together with β-Caryophyllene for 24 h and analysed for cell proliferation with MTT assay. ELISA based kit was used to determine apoptotic DNA fragmentation. Western blotting was used to determine expression levels of target proteins. The induction of experimental lung tumor in rat model was achieved through the injection of A549 tumor cells subcutaneously into the middle left side of the mice after anesthetization with pentobarbital (35 mg/kg) at 2.8 × 106 cells in 400 μl of PBS. Result: We found that β-Caryophyllene exerts the anti-proliferative effects on A549 cells. Furthermore, β-Caryophyllene significantly prevents apoptotic cell death and causes up-regulation of PGC-1α and TFAM compared to dexmedetomidine treated cells. We observed that β-Caryophyllene suppressed tumor development in mice significantly compared to dexmedetomidine treated group without changing body weight.

Mitotic kinesin-like protein 1, regulated by FOXM1, promotes triple negative breast cancer progression via activating Wnt/β-catenin pathway

Background: Triple negative breast cancer (TNBC) is highly malignant and has a worse prognosis, compared with other subtypes of breast cancer due to the absence of therapeutic targets. MKLP1 plays a crucial role in tumorigenesis and cancer progression. However, the role of MKLP1 in triple negative breast cancer and the underlying mechanism remain unknown. The study aimed to elucidate the biological function regulatory mechanism of MKLP1 in triple negative breast cancerMethods: Quantitative real-time PCR and Western blotting were used to determine the MKLP1 expression in breast cancer tissues and cell lines. Then, functional experiments in vitro and in vivo were performed to investigate the effects of MKLP1 on tumor growth and metastasis in triple negative breast cancer. Chromatin immunoprecipitation assay was conducted to illustrate the potential regulatory mechanisms of MKLP1 in triple negative breast cancer.Results: We found that MKLP1 was significantly up-regulated and associated with poor prognosis in triple negative breast cancer. MKLP1 could promote triple negative breast cancer proliferation, migration and invasion in vitro and in vivo. MKLP1 could activate Wnt/β-catenin pathway and promote EMT progression. In addition, FOXM1, upregulated by WDR5 via H3K4me3 modification, directly bound to the promoter of MKLP1 gene to promote its transcription and accelerated TNBC progression via Wnt/β-catenin pathway. Both of small inhibitor of FOXM1 and WDR5 could inhibit TNBC progression. Conclusions: Our findings elucidate WDR5/FOXM1/MKLP1/Wnt/β-catenin axis is associated with TNBC progression and may provide a novel and promising therapeutic target for TNBC treatment.

lncRNA GAS5 Sensitizes Breast Cancer Cells to Ionizing Radiation by Inhibiting DNA Repair

Radioresistance of breast cancer is a major reason for therapeutic failure and limits further increases in the dose of radiation due to severe adverse effects. Recently, long noncoding RNAs (lncRNAs) have been shown to regulate cancer proliferation, chemoresistance, and radioresistance. Among these lncRNAs, lncRNA GAS5 expression was shown to be downregulated in breast cancer and related to trastuzumab resistance. However, its role in the radiation response is unclear. In this study, we demonstrated that lncRNA GAS5 expression was reduced in irradiated cells and that overexpression of GAS5 reduced cell viability and promoted cell apoptosis after irradiation. Moreover, overexpression of GAS5 resulted in increased G2/M arrest and unrepaired DNA damage, indicating a radiosensitizing role of GAS5 in breast cancer cells. Finally, we found that a GAS5-interacting miRNA, miR-21, reversed the radiosensitizing effects of GAS5 by inhibiting the apoptotic pathway. In conclusion, we found that lncRNA GAS5 sensitized breast cancer cells to ionizing radiation by inhibiting DNA repair and suppressing miR-21, identifying novel targets for breast cancer radiosensitization.

Baicalin-loaded folic acid-modified albumin nanoparticles (FA-BSANPs/BA) induce autophagy in MCF-7 cells via ROS-mediated p38 MAPK and Akt/mTOR pathway

Background Breast cancer is the most frequently occurring cancer among women. Baicalin has been shown to inhibit breast cancer proliferation, but poor aqueous solubility and unknown mechanism of action limit its application. This study aimed to investigate the antiproliferative effects of baicalin-loaded folic acid-modified albumin nanoparticles (FA-BSANPs/BA) in breast cancer MCF-7 cells and its relationship with autophagy and ROS-mediated p38 MAPK and Akt/mTOR signaling pathways. Cell viability was detected by MTT assay. Flow cytometry and fluorescence microscopy were used to detect cell cycle, apoptosis and autophagy. Western blot was used to detect protein expression. Results Compared with the control and free baicalin groups, FA-BSANPs/BA inhibited viability of MCF-7 cells and increased cells in S phase, apoptotic bodies, pro-apoptotic proteins, autophagy markers and autophagosomes. These effects could be reversed when combined with the autophagy inhibitor 3-methyladenine. FA-BSANPs/BA increased the levels of phosphorylated p38 MAPK, inhibited the levels of phosphorylated Akt and mTOR, and increased the level of ROS in MCF-7 cells. The effects of FA-BSANPs/BA could be reversed or enhanced using inhibitors of Akt, mTOR, p38 MAPK and ROS scavengers. Conclusions Encapsulation in folate albumin nanoparticles improved the antiproliferative activity of baicalin. FA-BSANPs/BA induced autophagy and apoptosis via ROS-mediated p38 MAPK and Akt/mTOR signaling pathways in human breast cancer cells.

circ_0035277 Promotes Gastric Cancer Proliferation and Metastasis via miR-576-3p/LIN28B Axis

Circular RNAs (circRNAs) regulate biological processes of human tumours. Gastric cancer is a prevalent disease that presents tumours with high metastasis. This study aimed to understand regulatory function and mechanism of circ_0035277 in gastric cancer development. circ_0035277 level in tissues and cells was assessed using RT-qPCR assay. Function of circ_0035277 was evaluated via CCK-8, colony formation and Transwell assays. Location of circ_0035277 was verified with FISH assay. Potential mechanism of circ_0035277 was examined using bioinformatics and luciferase reporter assays. BALB/c nude mice were utilised to construct the gastric cancer metastasis model with subcutaneous injection. Haematoxylin–eosin staining was performed to measure visible tumour nodules in lung tissues. Results showed that circ_0035277 is significantly up-regulated in tissues and cell lines of gastric cancer, accelerates the deterioration of gastric cancer, is significantly located in the cytoplasm and serves as a sponge to participate in gastric cancer by targeting miR-576-3p. Furthermore, lin-28 homolog B (LIN28B) was a direct target of miR-576-3p and reversed the role of circ_0035277/miR-576-3p on gastric cancer metastasis. In vivo studies have shown that knockdown of circ_0035277 suppresses gastric cancer metastasis. Overall, circ_0035277 accelerated gastric cancer progression and metastasis by regulating miR-576-3p/LIN28B axis. These findings can provide a potential target for the treatment of gastric cancer.

The Role of Neuropeptide-Stimulated cAMP-EPACs Signalling in Cancer Cells

Neuropeptides are autocrine and paracrine signalling factors and mainly bind to G protein-coupled receptors (GPCRs) to trigger intracellular secondary messenger release including adenosine 3′, 5′-cyclic monophosphate (cAMP), thus modulating cancer progress in different kind of tumours. As one of the downstream effectors of cAMP, exchange proteins directly activated by cAMP (EPACs) play dual roles in cancer proliferation and metastasis. More evidence about the relationship between neuropeptides and EPAC pathways have been proposed for their potential role in cancer development; hence, this review focuses on the role of neuropeptide/GPCR system modulation of cAMP/EPACs pathways in cancers. The correlated downstream pathways between neuropeptides and EPACs in cancer cell proliferation, migration, and metastasis is discussed to glimmer the direction of future research.

CLDN6 Suppresses c–MYC–Mediated Aerobic Glycolysis to Inhibit Proliferation by TAZ in Breast Cancer

Claudin 6 (CLDN6) was found to be a breast cancer suppressor gene, which is lowly expressed in breast cancer and inhibits breast cancer cell proliferation upon overexpression. However, the mechanism by which CLDN6 inhibits breast cancer proliferation is unclear. Here, we investigated this issue and elucidated the molecular mechanisms by which CLDN6 inhibits breast cancer proliferation. First, we verified that CLDN6 was lowly expressed in breast cancer tissues and that patients with lower CLDN6 expression had a worse prognosis. Next, we confirmed that CLDN6 inhibited breast cancer proliferation through in vitro and in vivo experiments. As for the mechanism, we found that CLDN6 inhibited c–MYC–mediated aerobic glycolysis based on a metabolomic analysis of CLDN6 affecting cellular lactate levels. CLDN6 interacted with a transcriptional co–activator with PDZ-binding motif (TAZ) and reduced the level of TAZ, thereby suppressing c–MYC transcription, which led to a reduction in glucose uptake and lactate production. Considered together, our results suggested that CLDN6 suppressed c–MYC–mediated aerobic glycolysis to inhibit the proliferation of breast cancer by TAZ, which indicated that CLDN6 acted as a novel regulator of aerobic glycolysis and provided a theoretical basis for CLDN6 as a biomarker of progression in breast cancer.