ABSTRACT
Objective By analyzing mitochondrial function, reactive oxygen species (ROS) and adenosine triphosphate (ATP) production under different levels of RalA and caveolin-1 (Cav-1) expression, to investigate the regulation role of RalA played in cancer metabolism and explore the possibility of its regulation role involved in Cav-1 and caveolae motility. Methods Firstly, RalA and Cav-1 expression were inhibited by siRNA in breast cancer cell line MDA-MB-231, and then the changes of mitochondrial membrane potential (MMP), ROS production, ATP generation and L-lactate level before and after inhibition were assessed by Western blotting, confocal microscope and fluorescence quantification. Results (1) The decreased RalA and Cav-1 expression led to a significant reduction of MMP directly. (2) Low RalA and Cav-1 expression resulted in an inhibition of ATP production and an increase of H2O2 generation. With the reduction of MMP, mitochondrial malfunction was observed. (3) With mitochondrial function suppression, an elevated level of glycolysis metabolite L-lactate was also detected in RalA and Cav-1 deprived cells. Conclusions RalA and Cav-1 mediate cellular metabolic switch by inhibiting mitochondrial function and simultaneously boosting glycolysis. This regulation role of RalA depends on its association with Cav-1, and possibly is related to the endocytosis and motility of caveolae. The research findings enrich the cancer metabolic studies, and provide a novel approach for cancer therapeutic strategy targeted to cellular metabolism.
ABSTRACT
Objective By analyzing mitochondrial function,reactive oxygen species (ROS) and adenosine triphosphate (ATP) production under different levels of RalA and caveolin-1 (Cav-1) expression,to investigate the regulation role of RalA played in cancer metabolism and explore the possibility of its regulation role involved in Cav-1 and caveolae motility.Methods Firstly,RalA and Cav-1 expression were inhibited by siRNA in breast cancer cell line MDA-MB-231,and then the changes of mitochondrial membrane potential (MMP),ROS produc tion,ATP generation and L-lactate level before and after inhibition were assessed by Western blotting,confocal microscope and fluorescence quantification.Results (1) The decreased RalA and Cav-1 expression led to a significant reduction of MMP directly.(2) Low RalA and Cav-1 expression resulted in an inhibition of ATP production and an increase of H2O2 generation.With the reduction of MMP,mitochondrial malfunction was observed.(3) With mitochondrial function suppression,an elevated level of glycolysis metabolite L-lactate was also detected in RalA and Cav-1 deprived cells.Conclusions RalA and Cav-1 mediate cellular metabolic switch by inhibiting mitochondrial function and simultaneously boosting glycolysis.This regulation role of RalA depends on its association with Cav-1,and possibly is related to the endocytosis and motility of caveolae.The research findings enrich the cancer metabolic studies,and provide a novel approach for cancer therapeutic strategy targeted to cellular metabolism.
ABSTRACT
Notch-1 signaling pathway is responsible for cell differentiation, development, proliferation and apoptosis. Recent studies show that Notch-1 signaling pathway is also involved in cancer progression, including cell invasion, motility and cancer metastasis. Activation of Notch-1 signaling pathway can directly or indirectly induce cell proliferation and migration. In tumor cells, activation of Notch-1 facilitates epithelial-mesenchymal transition (EMT), keeps its mesenchyme characteristics and induces cell adhesion. Notch-1 signaling pathway also cross-talks with other pathways to regulate cell fate, such as PI3K/Akt, NF-κB pathways. The evidence shows that aberrant Notch-1 activation has been found in different solid tumors, which participates in regulating tumor metastasis. In this review, the Notch structure and function, Notch-1 signal and tumorigenesis, tumor metastasis via Notch-1 signaling, and Notch-1 signaling targeted-therapy were comprehensively summarized. To clarify the roles of Notch-1 signal pathway in tumor metastasis and its regulatory mechanisms as well as the current treatment strategies for Notch-1 signal pathway will provide references for studies on pathomechanism and clinical treatment of cancers.
ABSTRACT
Hematogenous metastasis is one of the most important ways for metastasis of tumor cells and this is a complex pathophysiological process. Tumor cells enter the bloodstream and move with the blood circulation, meanwhile interact with leukocyte, platelets via integrins, or directly interact with endothelial cells to cause a series of biological behaviors and promote the metastasis of tumor cells. These activated integrins, collaborating with other molecules (e.g. integrins, selectins, cytokines and chemokines), will induce various signal cascades to mediate tumor cell adhesion and migration, and form a new metastatic foci. Hence, better understanding of hematogenous metastasis process is of great significance for treating malignant metastasis of tumor cells and improving life of tumor patients. In this review, the roles of integrins during hematogenous metastasis of tumor cells and their signal transduction were summarized, and new perspectives for future investigation were also discussed. The elucidation about the mechanism of hematogenous metastasis of tumor cells will help to provide a rational basis for anticancer drug development and drug target discovery.
ABSTRACT
<p><b>OBJECTIVE</b>To establish an animal model of congenital heart defect with decreased pulmonary blood flow for better understanding the pathophysiology of pulmonary vascular development and related regulatory mechanisms of congenital heart defect with decreased pulmonary blood flow.</p><p><b>METHOD</b>One to two months old pigs were randomly divided into three groups: control group (group C, n = 6) with right chest small incisions induced transient pulmonary blood reduction; light-moderate stenosis groups (group T(1), n = 7): artificial atrial septum defect (ASD) plus controlled pulmonary artery banding to generate a systolic pressure gradient of 20 - 30 mm Hg (1 mm Hg = 0.133 kPa); severe stenosis groups (group T(2), n = 7): similar surgical procedures as group T(1), and controlled pulmonary artery banding to generate a systolic pressure gradient ≥ 30 - 50 mm Hg. 64-slice computed tomography scanning was performed at one month post operation. Arterial blood gas analysis, hemoglobin value, pulmonary vessel, ASD and banding ring diameters and trans-pulmonary artery banding pressure (Trans-PABP) were determined at two months post operation.</p><p><b>RESULTS</b>One pig died due to tracheal intubation accident in the C group, one pig died due to bowel obstruction in the T(1) group and two pigs died due to acute right heart failure and chronic heart failure respectively in T(2) group. 64-slice CT angiography results showed that aortic diameter of T(1) group was significantly lower than that of C group and banding diameter was significantly lower than aortic diameter in the T(1) and T(2) groups at one month post operation. Two months after operation, the size of ASD were (8.0 ± 0.5) mm and (8.9 ± 1.4) mm (P > 0.05) respectively in the T(1) and T(2) groups after operation. The Trans-PABP was significantly higher in the T(1) and T(2) groups than in C group (P < 0.01), and the Trans-PABP was significantly higher in the T(2) group than in T(1) group (P < 0.01). PaO2 and SaO2 in the T(1) and T(2) groups were significantly lower than those in C group.</p><p><b>CONCLUSION</b>Artificial atrial septum defect combined pulmonary artery banding procedures could be successfully used to establish model of congenital heart defect with decreased pulmonary blood flow and this model could help to understand the pathophysiology and monitor therapy efficacy for patients with congenital heart defect with decreased pulmonary blood flow.</p>