Mechanical regulation of cancer cell apoptosis and autophagy: Roles of bone morphogenetic protein receptor, Smad1/5, and p38 MAPK

AbstractMechanical forces induced by interstitial fluid flow in and surrounding tissues and by blood/lymphatic flow in vessels may modulate cancer cell invasion and metastasis and anticancer drug delivery. Our previous study demonstrated that laminar flow-induced shear stress induces G2/M arrest in tumor cells. However, whether shear stress modulates final cell fate remains unclear. In this study, we investigated the role of flow-induced shear stress in modulating the survival of four human tumor cell lines, i.e., Hep3B hepatocarcinoma cells, MG63 osteosarcoma cells, SCC25 oral squamous carcinoma cells, and A549 carcinomic alveolar basal epithelial cells. Laminar shear stress (LSS) ranging from 0.5 to 12dyn/cm2 induced death of these four tumor cell lines. In contrast to LSS at 0.5dyn/cm2, oscillatory shear stress (OSS) at 0.5±4dyn/cm2 cannot induce cancer cell death. Both LSS and OSS had no effect on human normal hepatocyte, lung epithelial, and endothelial cells. Application of LSS to these four cell lines increased the percentage of cells stained positively for annexin V–FITC, with up-regulations of cleaved caspase-8, -9, and -3, and PARP. In addition, LSS also induced Hep3B cell autophagy, as detected by acidic vesicular organelle formation, LC3B transformation, and p62/SQSTM1 degradation. By transfecting with small interfering RNA, we found that the shear-induced apoptosis and autophagy are mediated by bone morphogenetic protein receptor type (BMPR)-IB, BMPR-specific Smad1 and Smad5, and p38 mitogen-activated protein kinase in Hep3B cells. Our findings provide insights into the molecular mechanisms by which shear stress induces apoptosis and autophagy in tumor cells

Reduced Ca2+ transport across sarcolemma but enhanced spontaneous activity in cardiomyocytes isolated from left atrium-pulmonary veins tissue of myopathic hamster

<p>Abstract</p> <p>Background</p> <p>Several lines of evidence point to a particularly important role of the left atrium (LA) in initiating and maintaining atrial fibrillation (AF). This role may be related to the location of pulmonary veins (PVs) in the LA. The aim of the present study was to investigate the action potential (AP) and ionic currents in LA-PV cardiomyocytes isolated from Bio14.6 myopathic Syrian hamsters (36-57 week-old) versus age-matched F1B healthy control hamsters.</p> <p>Methods and Results</p> <p>Whole-cell patch-clamp techniques were used to record AP in current-clamp mode and ionic currents in voltage-clamp mode. The results obtained show that in both healthy and myopathic LA-PV tissue spontaneously discharging cardiomyocytes can be found, but they are more numerous in myopathic (9/29) than in healthy hamsters (4/42, p < 0.05 by χ²analysis). Myopathic myocytes have shorter AP duration (APD) with smaller I_Ca,Land I_NCXthan the healthy control. The currents I_TO, I_K, I_K1and I_Ca,Tare not significantly different in myopathic versus healthy cells.</p> <p>Conclusions</p> <p>Our results indicate that in myopathic Syrian hamsters LA-PV cardiomyocytes are more prone to automatic rhythms. Also, they show altered electrophysiologic properties, which may be due to abnormal Ca²⁺channels and may account for contractile dysfunction.</p

Ultraquantum magnetoresistance in Kramers Weyl semimetal candidate β\beta-Ag2Se

The topological semimetal $\beta$-Ag2Se features a Kramers Weyl node at the origin in momentum space and a quadruplet of spinless Weyl nodes, which are annihilated by spin-orbit coupling. We show that single crystalline $\beta$-Ag2Se manifests giant Shubnikov-de Haas oscillations in the longitudinal magnetoresistance which stem from a small electron pocket that can be driven beyond the quantum limit by a field less than 9 T. This small electron pocket is a remainder of the spin-orbit annihilatedWeyl nodes and thus encloses a Berry-phase structure. Moreover, we observed a negative longitudinal magnetoresistance when the magnetic field is beyond the quantum limit. Our experimental findings are complemented by thorough theoretical band structure analyses of this Kramers Weyl semimetal candidate, including first-principle calculations and an effective k*p model.Comment: A new version based on arXiv:1502.0232

Differential evolutionary conservation of motif modes in the yeast protein interaction network

BACKGROUND: The importance of a network motif (a recurring interconnected pattern of special topology which is over-represented in a biological network) lies in its position in the hierarchy between the protein molecule and the module in a protein-protein interaction network. Until now, however, the methods available have greatly restricted the scope of research. While they have focused on the analysis in the resolution of a motif topology, they have not been able to distinguish particular motifs of the same topology in a protein-protein interaction network. RESULTS: We have been able to assign the molecular function annotations of Gene Ontology to each protein in the protein-protein interactions of Saccharomyces cerevisiae. For various motif topologies, we have developed an algorithm, enabling us to unveil one million "motif modes", each of which features a unique topological combination of molecular functions. To our surprise, the conservation ratio, i.e., the extent of the evolutionary constraints upon the motif modes of the same motif topology, varies significantly, clearly indicative of distinct differences in the evolutionary constraints upon motifs of the same motif topology. Equally important, for all motif modes, we have found a power-law distribution of the motif counts on each motif mode. We postulate that motif modes may very well represent the evolutionary-conserved topological units of a protein interaction network. CONCLUSION: For the first time, the motifs of a protein interaction network have been investigated beyond the scope of motif topology. The motif modes determined in this study have not only enabled us to differentiate among different evolutionary constraints on motifs of the same topology but have also opened up new avenues through which protein interaction networks can be analyzed