P70 S6 kinase in the control of actin cytoskeleton dynamics and directed migration of ovarian cancer cells

Ovarian cancer is highly metastatic with a poor prognosis. The serine/threonine kinase, p70 S6 kinase (p70 S6K), which is a downstream effector of phosphatidylinositol 3-kinase/Akt pathway, is frequently activated in ovarian cancer. Here, we show that p70 S6K is a critical regulator of the actin cytoskeleton in the acquisition of the metastatic phenotype. This regulation is through two important activities: p70 S6K acts as an actin filament cross-linking protein and as a Rho family GTPase-activating protein. Ectopic expression of constitutively active p70 S6K in ovarian cancer cells induced a marked reorganization of the actin cytoskeleton and promoted directional cell migration. Using cosedimentation and differential sedimentation assays, p70 S6K was found to directly bind to and cross-link actin filaments. Immunofluorescence studies showed p70 S6K colocalized with cytochalasin D-sensitive actin at the leading edge of motile cells. The p70 S6K did not affect the kinetics of spontaneous actin polymerization, but could stabilize actin filaments by the inhibition of cofilin-induced actin depolymerization. In addition, we showed that p70 S6K stimulated the rapid activation of both Rac1 and Cdc42, and their downstream effector p21-activated kinase (PAK1), but not RhoA. Depletion of p70 S6K expression or inhibition of its activity resulted in significant inhibition of actin cytoskeleton reorganization and reduced migration, with a concomitant reduction in Rac1, Cdc42 and PAK1 activation, confirming that the effect was p70 S6K specific. Similarly, the actin cytoskeleton reorganization/migratory phenotype could be reversed by expression of dominant negative Rac1 and Cdc42, or inhibition of PAK1. These results reveal a new direction for understanding the oncogenic roles of p70 S6K in tumor progression. © 2011 Macmillan Publishers Limited All rights reserved.postprin

Influence of Maternal Infection and Pregnancy Complications on Cord Blood Telomere Length

BACKGROUND: Exposure to suboptimal intrauterine environment might induce structural and functional changes that can affect neonatal health. Telomere length as an important indicator of cellular health has been associated with increased risk for disease development. OBJECTIVES: This study was aimed to examine the independent and combined effects of maternal, obstetric, and foetal factors on cord blood telomere length (TL). METHODS: Pregnant women at the gestational age of 20th to 24th week who attended the antenatal clinic of a major local hospital in Hong Kong were recruited. Participants were asked to complete a questionnaire on demographics, health-related quality of life, and history of risk behaviors. Medical history including pregnancy complications and neonatal outcomes was obtained from electronic medical records of both mother and neonate. Umbilical cord blood was collected at delivery for TL determination. RESULTS: A total of 753 pregnant women (average age: 32:18 ± 4:51 years) were recruited. The prevalence of maternal infection, anaemia, and hypertension during pregnancy was 30.8%, 30.0%, and 6.0%, respectively. The adjusted regression model displayed that maternal infection was negatively associated with cord blood TL (β = −0:18, p = 0:026). This association became even stronger in the presence of antenatal anaemia, hypertension, delivery complications, or neonatal jaundice (β = −0:25 to −0.45). Conclusions. This study consolidates evidence on the impact of adverse intrauterine environment at the cellular level. Maternal infection was significantly associated with shorter cord blood TL in a unique manner such that its presence may critically determine the susceptibility of telomere to other factors

p70 S6 kinase regulates the actin cytoskeleton in ovarian cancer cell motility by binding and cross-linking actin filaments

Poster Session 11 - Adhesion and Cytoskeletal Signaling in Invasion: abstract no. 5116p70 S6 kinase (p70S6K) is a downstream effector of phosphatidylinositol 3-kinase and is frequently activated in human ovarian cancer. Here we show for the first time that p70S6K functions in actin cytoskeleton reorganization responsible for the acquisition of invasiveness during tumor progression. Ectopic expression of active p70S6K in ovarian cancer cells induced dramatic reorganization of the actin cytoskeleton and promoted cell migration. Inhibition of p70S6K by siRNA or small molecule inhibitor resulted in diminished cell migration and actin cytoskeleton reorganization, confirming that these effects were p70S6K specific. By using cosedimentation and differential sedimentation assays, p70S6K was found to bind actin filaments, and was more effective in the presence than in the absence of phosphorylation. Importantly, purified p70S6K could be cosedimented with purified filamentous actin, indicating a direct association between p70S6K and actin. The response to p70S6K could be blocked with cytochalasin D, indicating that the binding of p70S6K to the cytoskeleton is mediated by actin. In addition, our results suggest that this is a functional interaction, because p70S6K was capable of generating specialized, actin-based cell morphologies via direct cross-linking activity. This bundling activity was confirmed by light scattering and electron microscopy. These results, in conjunction with our prior evidence that p70S6K regulates Rac and Cdc42 GTPases, suggest that p70S6K serves as an important regulator of the actin cytoskeleton, highlighting a role for p70S6K in the regulation of tumor progression and metastasis in ovarian cancer.link_to_OA_fulltextThe 101st Annual Meeting of the American Association for Cancer Research (AACR 2010), Washington D.C., 17-21 April 2010. In AACR Meeting Abstracts, 201

Exploiting p70 S6 kinase as a target for ovarian cancer

The p70 S6 kinase (p70 S6K) is frequently active in ovarian and a wide range of cancer types, and it has a crucial role in several processes considered hallmarks of cancer. Therefore, blocking p70 S6K expression or activity may present a promising strategy for anticancer treatment. Areas covered: The current understanding of the molecular mechanisms that govern p70 S6K regulation as well as its tumorigenic effects, which are involved in the initiation and progression in ovarian cancer, in particular the emerging new role of p70 S6K in cell migration, which is a prerequisite of tumor metastasis. The p70 S6K cellular substrates and/or interacting proteins. The current state of drugs that target this kinase, either alone or in combination with other targeted agents. Expert opinion: Targeting p70 S6K through the use of small-molecule inhibitors, microRNAs and natural compounds may represent a beneficial new avenue for cancer therapy and opens new areas of investigation in p70 S6K biology. © 2012 Informa UK, Ltd.link_to_subscribed_fulltex

Hepatocyte growth factor phosphorylates p70 S6 kinase to regulate Rac1 and Cdc42 and promote ovarian cancer cell migration and invasion

Conference Theme: Science, Synergy, and SuccessOvarian cancer is the most lethal gynecological cancer. The hepatocyte growth factor (HGF) receptor Met is a receptor tyrosine kinase that is frequently overexpressed in ovarian cancer and correlates with poor prognosis. However, the molecular mechanisms responsible are still poorly understood. Our recent findings show for the first time that activation of p70 S6 kinase (p70S6K) downstream of phosphatidylinositol 3-kinase is a key step for HGF-induced invasion and migration of ovarian cancer cells. In this study, we showed that ectopic expression of active p70S6K induced dramatic reorganization of the actin cytoskeleton. This effect was associated with activation of two members of the Rho family of GTPases, Rac1 and Cdc42, but not RhoA. Inhibition of p70S6K by a specific inhibitor or small interfering RNA abolished the HGF-stimulated migratory phenotype with a concomitant reduction in Rac1 and Cdc42 activation, confirming the effect was p70S6K specific. Overexpression of constitutively active forms of Rac1 and Cdc42 were sufficient to induce cell migration, whereas dominant negative mutants of Rac1 and Cdc42 inhibited p70S6K-induced motogenic signal. Importantly, we showed that active p70S6K co-precipitated with F-actin in vitro. Immunofluorescence experiments confirmed that active p70S6K colocalized in vivo with the actin filaments. These results identify a novel mechanism in HGF-induced cellular invasion and migration, which is mediated by p70S6K through regulation of the actin cytoskeleton by Rho GTPases (This work is supported by Hong Kong Research Grants Council Grant HKU7599/05M to A.S.T.W.).link_to_OA_fulltex

Issues in pulmonary function testing for the screening and diagnosis of chronic obstructive pulmonary disease

PURPOSE OF REVIEW: The purpose of this review article is to provide an up-to-date summary on the current evidence for or against the use of lung function tests as screening and diagnostic tools for airflow obstruction in chronic obstructive pulmonary disease (COPD), and to consider the relevant issues in context. RECENT FINDINGS: COPD is characterized by chronic respiratory symptoms and airflow limitation with only partial reversibility on lung function testing. However, screening on a population basis or of an enriched 'at-risk' subset like chronic smokers is not supported by findings from previous epidemiological studies, screening trials or in currently published clinical management guidelines by professional societies and review bodies. The definition of airflow obstruction and the classification of disease severity of COPD also differ slightly between guidelines and statements from different professional societies. SUMMARY: Given the experience from previous screening trials and controversial classification of airflow obstruction by severity, it is impossible to have accurate screening results for COPD based on lung function tests alone. Clinical respiratory symptoms should be taken into consideration in terms of the diagnosis and management of COPD, as well as in any screening trial or programme that is to be attempted or implemented. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.link_to_subscribed_fulltex

p70 S6 kinase signals tristetraprolin/Dicer-mediated maturation of microRNA-145 to regulate tumor metastasis

Session - Molecular and Cellular Biology: Poster Presentations - MicroRNAs and Metastasis: abstract no. 1449Meeting Theme: Harnessing Breakthroughs - Targeting CuresThis journal suppl. entitled: Proceedings: AACR Annual Meeting 2014Ovarian cancer is a highly metastatic tumor characterized by malignant ascites spheroids, which represent one of the most important prognostic factors of poor clinical outcome. Multicellular aggregates known as spheroids (MCS) are important for anchorage-independent growth and metastasis. MCS are also an important phenomenon of cancer stem cells. However, the factors that regulate MCS formation are largely unknown. MicroRNAs (miRNA) are short non-coding RNAs that are critically involved in different oncogenic events by actively modulating mRNA and protein synthesis. Despite their clinical significance, processes regulating miRNA biogenesis remain obscure. Here, we identify N-cadherin as a key regulator of MCS formation activated in response to p70 S6 kinase (p70S6K) signaling, a downstream effector of phosphatidylinositol 3-kinase/Akt which is hyperactive in human ovarian cancer. The results also identify a new mechanism of p70S6K function that mediates microRNA (miR)-145 coregulation of key transcription factors Twist and Sox-9, thereby enhancing N-cadherin and MCS formation. p70S6K regulates miR-145 by deactivating a distinct tristetraprolin (TPP)/Dicer program. The p70S6K phosphorylates TTP, leading to inhibition of interaction between TTP and Dicer and decreased TTP activity in miR-145 processing. Silencing of p70S6K enhances the TTP/Dicer interaction and its activating in regulating miR-145. These results providea novel regulatory mechanism of p70S6K involved in the formation and spread of MCS and insights on the development of new therapeutic targets. (This work was supported by RGC grant HKU782111 and CUHK8/CRF/11R). ©2014 American Association for Cancer Research

Obstructive Sleep Apnea

Section 16: Respiratory sleep disorders - Chapter 121Sleep is a naturally occurring state characterized by altered consciousness, relatively inhibited sensory activity and inhibition of almost all voluntary muscles. The importance of sleep may be observed across mammals, birds, reptiles, amphibians, fish, some forms of insects and even in simple phyla such as nematodes suggesting that it is both universal and essential across the animal kingdom. Sleep disorders and related diseases are becoming increasingly relevant for health and well-being. These conditions affect different aspects of health, showing bidirectionality with a wide range of conditions and comorbidities. They have several negative consequences for the individual as well as the society on the whole in terms of health, loss in productivity and other social costs

Hepatocyte growth factor modulates adhesion of ovarian cancer cells to the peritoneum mesothelium through p70 S6 kinase

Poster Session 23 - Targeting Tumor Invasion: abstract no. 1527Ovarian cancer has the highest mortality of all gynecological cancers. These deaths are mainly due to the highly metastatic characteristic with already widespread peritoneal dissemination and malignant ascites at the time of diagnosis. However the molecular mechanisms that regulate ovarian cancer progression are poorly understood. A key step in this process is the adhesion of ovarian cancer cells to the peritoneal mesothelium. Hepatocyte growth factor (HGF) is present at ...link_to_OA_fulltextThe 102nd Annual Meeting of American Association for Cancer Research (AACR), Orlando, FL., 2-6 April 2011

Implementation of logistics information system to support reverse logistics - a case study

The carrying back of goods sold to the market has grown to be an important area of the logistics system for manufacturers today. Increased concern for the environment has led to new techniques to design products and supply chains that are both economically and ecologically feasible. The aim of this paper is to propose an infrastructure framework for supporting the design and implementation of a reverse logistics system. The first target is using the reverse logistics infrastructural framework to minimise the total logistics cost. The company should not only count the cost of forward logistics in terms of pushing the goods to the market, but also take into consideration the cost of taking the goods back to the point of origin. The second target is to set up the relevant information management tools to execute the reverse logistics activities at the minimum cost of additional expenses of the company. To validate the feasibility of the approach, a case study on a telecommunications services supply company has been conducted with promising results.Department of Industrial and Systems Engineerin