Negative regulation of signal transducer and activator of transcription-3 signalling cascade by lupeol inhibits growth and induces apoptosis in hepatocellular carcinoma cells

Background: Constitutive activation of signal transducer and activator of transcription signalling 3 (STAT3) has been linked with survival, proliferation and angiogenesis in a wide variety of malignancies including hepatocellular carcinoma (HCC). Methods: We evaluated the effect of lupeol on STAT3 signalling cascade and its regulated functional responses in HCC cells. Results: Lupeol suppressed constitutive activation of STAT3 phosphorylation at tyrosine 705 residue effectively in a dose- and time-dependent manner. The phosphorylation of Janus-activated kinases (JAKs) 1 and 2 and Src was also suppressed by lupeol. Pervanadate treatment reversed the downregulation of phospho-STAT3 induced by lupeol, thereby indicating the involvement of a phosphatase. Indeed, we observed that treatment with lupeol increased the protein and mRNA levels of SHP-2, and silencing of SHP-2 abolished the inhibitory effects of lupeol on STAT3 activation. Treatment with lupeol also downregulated the expression of diverse STAT3-regulated genes and decreased the binding of STAT3 to VEGF promoter. Moreover, the proliferation of various HCC cells was significantly suppressed by lupeol, being associated with substantial induction of apoptosis. Depletion of SHP-2 reversed the observed antiproliferative and pro-apoptotic effects of lupeol. Conclusions: Lupeol exhibited its potential anticancer effects in HCC through the downregulation of STAT3-induced pro-survival signalling cascade

Structural Modeling and DNA Binding Autoinhibition Analysis of Ergp55, a Critical Transcription Factor in Prostate Cancer

BACKGROUND: The Ergp55 protein belongs to Ets family of transcription factor. The Ets proteins are highly conserved in their DNA binding domain and involved in various development processes and regulation of cancer metabolism. To study the structure and DNA binding autoinhibition mechanism of Ergp55 protein, we have produced full length and smaller polypeptides of Ergp55 protein in E. coli and characterized using various biophysical techniques. RESULTS: The Ergp55 polypeptides contain large amount of α-helix and random coil structures as measured by circular dichorism spectroscopy. The full length Ergp55 forms a flexible and elongated molecule as revealed by molecular modeling, dynamics simulation and structural prediction algorithms. The binding analyses of Ergp55 polypeptides with target DNA sequences of E74 and cfos promoters indicate that longer fragments of Ergp55 (beyond the Ets domain) showed the evidence of auto-inhibition. This study also revealed the parts of Ergp55 protein that mediate auto-inhibition. SIGNIFICANCE: The current study will aid in designing the compounds that stabilize the inhibited form of Ergp55 and inhibit its binding to promoter DNA. It will contribute in the development of drugs targeting Ergp55 for the prostate cancer treatment

Genotoxicity assessment of a pharmaceutical effluent using four bioassays

Pharmaceutical industries are among the major contributors to industrial waste. Their effluents when wrongly handled and disposed of endanger both human and environmental health. In this study, we investigated the potential genotoxicity of a pharmaceutical effluent, by using the Allium cepa, mouse- sperm morphology, bone marrow chromosome aberration (CA) and micronucleus (MN) assays. Some of the physico-chemical properties of the effluent were also determined. The A. cepa and the animal assays were respectively carried out at concentrations of 0.5, 1, 2.5, 5 and 10%; and 1, 5, 10, 25 and 50% of the effluent. There was a statistically different (p < 0.05), concentration-dependent inhibition of onion root growth and mitotic index, and induction of chromosomal aberrations in the onion and mouse CA test. Assessment of sperm shape showed that the fraction of the sperm that was abnormal in shape was significantly (p < 0.05) greater than the negative control value. MN analysis showed a dose-dependent induction of micronucleated polychromatic erythrocytes across the treatment groups. These observations were provoked by the toxic and genotoxic constituents present in test samples. The tested pharmaceutical effluent is a potentially genotoxic agent and germ cell mutagen, and may induce adverse health effects in exposed individuals

Perceived managerial and leadership effectiveness in a Korean context: An indigenous qualitative study

Multinational corporations (MNCs) across the world have sent an increasing number of managers abroad to leverage unprecedented opportunities in the era of globalization. However, their failure rate has been above 33% for decades, resulting in substantial costs (Puck, Kittler, & Wright, 2008). One of the primary reasons for this failure is a lack of understanding of the national and organizational cultures within the host countries (Festing & Maletzky, 2011). For example, while a number of MNCs have entered the Korean market, several such as Yahoo, Motorola, and Walmart have failed and withdrawn due to the companies’ lack of adjustment to the Korean cultural context (Choe, 2006; Woo, 2013). In spite of the significance of culturally embedded practices, most researchers who have explored management and leadership in Asian countries, whether they were Western or indigenous researchers, have implemented studies using extant Western management and leadership theories derived within the Western cultural context (Leung, 2007; Tsui, 2006). Numerous scholars have claimed that this could be problematic because the findings of such studies may not be applicable to non-Western countries (Li, 2012; Liden & Antonakis, 2009), and may fail to provide insights and understanding of novel contexts or to reveal indigenous aspects of management and leadership (Tsui, 2007). Consequently, there have been increasing calls for indigenous management and leadership research within Asian countries (see Li et al., 2014; Lyles, 2009; Tsui, 2004; Wolfgramm, Spiller, & Voyageur, 2014). Over the past 30 years, managerial effectiveness and leadership effectiveness have been substantially neglected areas of management research (Noordegraaf & Stewart, 2000; Yukl, Gordon, & Taber, 2002). In addition, there has been little agreement on what specific behaviors distinguish effective managers from ineffective ones. Furthermore, more research is needed to examine the managerial and leadership behaviors that are critical for shaping the performance of individuals, groups and organizations (see Borman & Brush, 1993; Cammock, Nilakant & Dakin, 1995; Mumford, 2011; Noordegraaf & Stewart, 2000; Yukl et al., 2002). While most of the research related to managerial and leadership effectiveness has been conducted in the U.S., the few notable non-U.S. studies include that of Cammock et al. (1995) in New Zealand who developed a behavioral lay model of managerial effectiveness using the repertory grid technique. Another notable exception is the cumulative series of perceived managerial and leadership effectiveness studies conducted by Hamlin with various indigenous co-researchers in Western and non-Western countries (see Hamlin & Patel, 2012; Ruiz, Wang, & Hamlin, 2013) using Flanagan’s (1954) critical incident technique (CIT)

Castration-resistant prostate cancer: potential targets and therapies

Aijaz Parray,1 Hifzur R Siddique,1 Sanjeev Nanda,1,2 Badrinath R Konety,3 Mohammad Saleem1,3,41Molecular Chemoprevention and Therapeutics, The Hormel Institute, University of Minnesota, Austin, 2Department of Internal Medicine, Mayo Clinic Health Systems, Austin, TX, 3Department of Urology, University of Minnesota, Minneapolis, 4Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USAAbstract: The treatment landscape for patients with castration-resistant prostate cancer (CRPC) is undergoing significant changes with the advent of new therapies and multidisciplinary efforts by scientists and clinicians. As activation of multiple molecular pathways in the neoplastic prostate makes it impossible for single-target drugs to be completely effective in treating CRPC, this has led to combination therapy strategy, where several molecules involved in tumor growth and disease progression are targeted by a therapeutic regimen. In the present review, we provide an update on the molecular pathways that play an important role in the pathogenesis of CRPC and discuss the current wave of new treatments to combat this lethal disease.Keywords: chemoresistance, CRPC, molecular pathways, neoplastic prostat