Biomedical subjects

Athanasios G Papavassiliou

Publications and source records attributed to Athanasios G Papavassiliou.

At least 37 records · Page 2Linked to original sources

PubMed2005

PPAR-gamma is expressed and NF-kB pathway is activated and correlates positively with COX-2 expression in stromal myofibroblasts surrounding colon adenocarcinomas.

PURPOSE: Accumulated evidence indicates that carcinogenesis is closely associated with the transformation of normal stroma into a 'reactive' stromal phenotype. The present study investigated the role of PPARgamma, COX-2 and p-IkB-alpha--important molecular targets of colon cancer chemoprevention--in this stromal remodeling by evaluating and comparing the expression of these factors in stromal myofibroblasts, macrophages and endothelial cells that surround normal colonic mucosa and colon cancer. METHODS: Immunohistochemical methodology was employed on archived paraffin-embedded sections prepared from tumors and adjacent normal colon from 45 patients with colon adenocarcinomas. Double immunostaining with the universal marker for myofibroblasts (alpha-smooth muscle actin/alpha-SMA) as second primary antibody was also performed. RESULTS: Stromal macrophages and endothelial cells expressed these factors both in normal colonic mucosa and colon cancer. By contrast, stromal myofibroblasts expressed PPARgamma, COX-2 and p-IkB-alpha only in colon adenocarcinomas (77.7%, 100% and 100% of cases, respectively) and not in normal colon. COX-2 and p-IkB-alpha expressions were strongly correlated in these cells (P < 0.001). PPARgamma, COX-2 and p-IkB-alpha expression did not correlate with the stage or differentiation of the adenocarcinomas. CONCLUSIONS: NF-kB pathway is activated and COX-2 expression is upregulated in stromal myofibroblasts surrounding colon adenocarcinomas compared to normal colon. Induction of COX-2 expression is primarily induced by NF-kB. NSAIDs, selective COX-2 inhibitors and PPARgamma ligands may exert their chemoprophylactic properties through direct actions on these cells.

Adenocarcinoma↗

PubMed2005

Statins and transcriptional regulation: the FXR connection.

Farnesoid X receptor (FXR) is a nuclear receptor involved in lipoprotein as well as glucose metabolism. Statins are widely used hypolipidemic agents with many pleiotropic actions. It is known that statins affect other nuclear hormone receptors, but no reports are available on the effect of these drugs on FXR. Employing an animal model (Syrian hamsters), we hereby present evidence to demonstrate that Simvastatin, a broadly prescribed statin, decreases the expression of FXR at both the RNA and protein levels and down-regulates its DNA-binding activity. This novel property may have important implications on the mode statins influence on lipoprotein and carbohydrate homeostasis in the organism.

Administration, Oral↗

PubMed2005

The gonadotropin-releasing hormone (GnRH)-1 gene, the GnRH receptor gene, and their promoters in patients with idiopathic hypogonadotropic hypogonadism with or without resistance to GnRH action.

The study included 26 patients with idiopathic hypogonadotropic hypogonadism (24 sporadic and 2 familial). The Pro146Ser mutation was identified in the gonadotropin-releasing hormone receptor (GnRHR) gene in two sisters as well as in their mother, and one polymorphism in the GnRH1 gene (the Trp16Ser) was identified in four patients. No mutations in transcription factor-binding sites of their promoters were identified. Three patients (one male and two sisters) were found with resistance to GnRH action. No mutations were identified in the male, whereas in the females the mutation Pro146Ser in the GnRHR was identified in heterozygosity.

Adult↗

PubMed2005

Retinoid receptor cross-talk in respiratory epithelium cancer chemoprevention.

The rationale for using retinoids in the prevention of respiratory epithelium cancers is based on their ability to coordinately regulate differentiation, proliferation and apoptosis. The complex retinoid signaling pathways and their cross-reactions are modulated by multiple mechanisms that are gradually being elucidated. It is possible that significant molecular changes take place during the very early stages of respiratory epithelial carcinogenesis, which enable cancer cells to escape apoptosis and result in unimpeded proliferation. Here, we propose that a "switch on/off" model dictates the cross-talk between retinoid receptors and other signal transducing pathways during respiratory epithelium carcinogenesis. This model might contribute to the development of novel selective retinoids and their clinical evaluation in combinatorial chemopreventive strategies.

Animals↗

PubMed2005

Novel insights into the implication of the IGF-1 network in prostate cancer.

Nearly a decade has passed since the hypothesis that the insulin-like growth factor (IGF) signalling cascade is involved in prostate carcinogenesis. Recent research has outlined the association of circulating IGF-1 and prostate cancer risk, and studies have elucidated the implication of the IGF network in the early stages of prostate carcinogenesis. Moreover, it has been suggested that IGF-1 induces ligand-independent activation of the androgen receptor and enhances the expression of matrix metalloproteinase-2 and urokinase plasminogen activator. Furthermore, progression to androgen independence has been linked to deregulation of the IGF-1-IGF-1-receptor axis. Here, we report on updated studies that contribute to the unravelling of the IGF 'circuitry' in prostate cancer cells, with the anticipation that relevant pharmacological 'rewiring' might offer novel therapeutic regimens.

Humans↗

PubMed2005

New therapeutic options for the metabolic syndrome: what's next?

The metabolic syndrome (MSX), characterized by obesity, insulin resistance, dyslipidemia and hypertension, increases the risk of cardiovascular morbidity and mortality. It has recently been hypothesized that MSX and type 2 diabetes are caused by triglyceride and long-chain fatty acid accumulation in liver, muscle, pancreatic islets and selected brain areas. This lipocentric approach is integrated with analysis of inflammation associated with end-organ damage, including the vascular wall. Genes and proteins contributing to insulin resistance, beta cell dysfunction and vascular wall damage have been identified. Transcription factors and coactivators, including peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator-1 are crucial in mediating insulin resistance and accelerating vascular wall inflammation, and represent promising therapeutic targets. New pharmacological strategies include dual PPARalpha/gamma agonists, drugs with pleiotropic effects or combination therapies.

Cardiovascular Diseases↗

PubMed2005

p53-dependent ICAM-1 overexpression in senescent human cells identified in atherosclerotic lesions.

Most normal somatic cells enter a state called replicative senescence after a certain number of divisions, characterized by irreversible growth arrest. Moreover, they express a pronounced inflammatory phenotype that could contribute to the aging process and the development of age-related pathologies. Among the molecules involved in the inflammatory response that are overexpressed in senescent cells and aged tissues is intercellular adhesion molecule-1 (ICAM-1). Furthermore, ICAM-1 is overexpressed in atherosclerosis, an age-related, chronic inflammatory disease. We have recently reported that the transcriptional activator p53 can trigger ICAM-1 expression in an nuclear factor-kappa B (NF-kappaB)-independent manner (Gorgoulis et al, EMBO J. 2003; 22: 1567-1578). As p53 exhibits an increased transcriptional activity in senescent cells, we investigated whether p53 activation is responsible for the senescence-associated ICAM-1 overexpression. To this end, we used two model systems of cellular senescence: (a) human fibroblasts and (b) conditionally immortalized human vascular smooth muscle cells. Here, we present evidence from both cell systems to support a p53-mediated ICAM-1 overexpression in senescent cells that is independent of NF-kappaB. We also demonstrate in atherosclerotic lesions the presence of cells coexpressing activated p53, ICAM-1, and stained with the senescence-associated beta-galactosidase, a biomarker of replicative senescence. Collectively, our data suggest a direct functional link between p53 and ICAM-1 in senescence and age-related disorders.

Arteriosclerosis↗

PubMed2005

Pharmacogenetic principles in the Hippocratic writings.

Twenty-five centuries after Hippocrates, we are at the beginning of an era of individualized, molecular, and genomic medicine, where diagnosis, prognosis, and treatment will be increasingly based on our understanding of the human organism's genetic and molecular composition. The most difficult task in this process has proven to be the application of the scientific advancements to the clinical setting, and clinical pharmacology is an essential discipline in this translational process. This article traces the roots of the emerging personalized and genome-based medicine to the teachings of Hippocrates.

Drug Therapy↗

PubMed2005

17-AAG: mechanisms of antitumour activity.

Heat-shock protein 90 (Hsp90) is a molecular chaperone involved in three-dimensional folding, intracellular translocation and degradation of multiple key regulatory proteins. Accumulated evidence has indicated an important role of Hsp90 in several signal transduction pathways that are deregulated in carcinogenesis. 17-allylamino-17-demethoxygeldanamycin (17-AAG), a selective inhibitor of Hsp90, is currently under clinical investigation in advanced malignancies in which Hsp90 client proteins are implicated. This article discusses the mechanistic evidence underlying 17-AAG's cytostatic, proapoptotic, antiangiogenic and anti-invasive properties that provide the basis for its antitumour activity and underscores its unique therapeutic potential as a multi-targeted agent, as opposed to most of the current-generation molecular therapeutics.

Animals↗

PubMed2005

Transcription factor therapeutics: long-shot or lodestone.

Many drugs, both approved and in development, exert their effects through transcription factors. The complexity of the biology of transcriptional regulation, however, presents challenges to the effective design of therapies that directly target transcription factors. This review focuses on the different approaches that are currently pursued in therapeutics and drug discovery aimed at targeting transcription factors and signaling molecules, and their areas of effect in transcription factor biology. A relatively recent approach termed "transcription therapy" has been applied for a number of drugs in development, which may potentially provide a new avenue for targeting transcription factors for therapeutic purposes.

Drug Design↗

PubMed2004

Growth hormone attenuates the transcriptional activity of Runx2 by facilitating its physical association with Stat3beta.

UNLABELLED: We document that GH controls osteoblast function by modulating the biological activity of the osteospecific transcription factor Runx2. Evidence is provided for a physical interaction between Runx2 and Stat3beta, which is enhanced by GH and downregulates the transcriptional properties of this key osteogenic regulator. INTRODUCTION: Growth hormone (GH) signals to bone either through insulin-like growth factor-1 or directly by influencing the function of osteoblasts, the bone-forming cells. This study aimed at exploring the molecular events that underlie the direct biological action of GH on osteoblastic cells, and specifically, the effects that it might exert on the function of the bone-specific transcriptional regulator Runx2. MATERIALS AND METHODS: The GH-responsive human osteoblastic cell line Saos-2 was used as our experimental system. Western blot analyses were used to monitor the presence of several parameters known to be affected by GH in these cells (i.e., downregulation of GH receptor, induction of STATs, and extracellular signal-regulated kinase [ERK] mitogen-activated protein kinase [MAPK] pathways). Electrophoretic mobility shift assays were used to assess Runx2 and Stat3 binding activity on an osteoblast-specific element (OSE2) after GH treatment. A combination of yeast two-hybrid and co-immunoprecipitation assays were performed to test for the existence of a physical Runx2.Stat3beta association. Finally, co-transfection experiments were used to investigate the interplay of the two transcription factors on the activity of a p6OSE2-Luc promoter after GH stimulation. RESULTS: We show that GH signaling through Stat3/ERK MAPK potentiates the DNA binding activity of Runx2 but, at the same time, restrains its transcriptional potential. Moreover, a novel physical interaction of Runx2 with transcription factor Stat3beta, which is enhanced by GH stimulation, was documented both in vitro and in vivo. Importantly, this interaction impairs the transcriptional activity of Runx2 without affecting its DNA binding capacity. CONCLUSION: Our data provide the first evidence that GH modulates the transcriptional function of Runx2 in osteoblastic cells by promoting its inhibitory interaction with Stat3beta. Shedding light on such mechanisms will contribute to a better understanding of GH effects on skeletal homeostasis that may impact on decisions at the clinical level, especially in diseases affecting bone quantity and quality (e.g., osteoporosis).

Blotting, Western↗

PubMed2004

Distinct expression patterns of the transcription factor E2F-1 in relation to tumour growth parameters in common human carcinomas.

E2F-1 is a pivotal transcription factor that integrates signals from a variety of G1/S phase regulators and modulates diverse cellular functions, such as DNA synthesis, repair, mitosis, and apoptosis. Its role in cellular proliferation and apoptosis, as depicted from experimental models and limited reports in human malignancies, remains a matter of debate. Recently, in non-small cell lung cancer, it was observed that E2F-1 overexpression was associated with tumour growth, implying an 'oncogenic' effect. To clarify further the role of E2F-1 in carcinogenesis, the investigation was expanded in four of the most common human malignancies by examining its expression status and putative impact on tumour kinetics. These issues were addressed by immunohistochemical and molecular means in 52 breast carcinomas, 42 prostate adenocarcinomas, 58 colon adenocarcinomas, and 77 superficial bladder transitional cell carcinomas (TCCs). The following results were found: (i). in breast carcinomas, E2F-1 expression correlated with proliferation (p < 0.001) and growth index (p = 0.001); (ii). in prostate adenocarcinomas, absence of E2F-1 was noted, in contrast to its expression in normal and hyperplastic glands; (iii). in colon adenocarcinomas, E2F-1 expression was inversely related to growth index (p = 0.001), being expressed in lesions with increased apoptosis (p = 0.001) and low proliferation (p < 0.001); and (iv) in superficial TCCs, E2F-1 expression correlated with proliferation (p = 0.002). Taken together, these results suggest that E2F-1 has a growth-promoting effect in breast carcinomas and superficial TCC, whereas the opposite seems to be the case for colon and prostate cancer. To interpret the above findings, the status of the pRb and p53 tumour suppressor pathways, which are known to affect E2F-1 activity, was further investigated. The results suggest that the actions of E2F-1 are mainly dependent on the functionality of these pathways. Nevertheless, the data also imply that p53-independent pathways may play a nodal role in the function of E2F-1 in colon cancer.

Adult↗

PubMed2004

Estrogen receptor beta (ERbeta) is expressed in brain astrocytic tumors and declines with dedifferentiation of the neoplasm.

PURPOSE: Estrogen receptor beta (ERbeta) is the second identified receptor mediating the effects of estrogen on target tissues. The role of ERbeta in cancer pathobiology is largely unknown, because specific antibodies have not been available until recently. Initial studies have shown that ERbeta expression declines in breast, ovarian, prostatic, and colon carcinomas. Tamoxifen, a synthetic anti-estrogen compound that is a mixed agonist/antagonist of estrogen receptor alpha (ERalpha) and a pure antagonist of ERbeta, has moderate beneficial effects in human astrocytic neoplasms. However, most published studies agree that glial tumors do not express ERalpha. The purpose of this study was to explore the expression of ERbeta in astrocytic neoplasms. METHODS: ERbeta expression was monitored immunohistochemically in 56 cases of astrocytomas of all grades (grade I-IV) and in adjacent non-neoplastic brain tissue. RESULTS: Moderate or strong nuclear immunopositivity was obtained in non-neoplastic astrocytes and in low-grade astrocytomas, whereas the majority of high-grade tumors were immunonegative or displayed weak immunoreactivity. The progressive decline in ERbeta expression paralleled the increase in tumor grade. CONCLUSIONS: In as much as ERbeta is possibly the only ER expressed in astrocytes, its decreased expression may play an important role in astrocytic tumor initiation and in the potential response of glial neoplasms to tamoxifen.

Adolescent↗

PubMed2004

Overexpression of the replication licensing regulators hCdt1 and hCdc6 characterizes a subset of non-small-cell lung carcinomas: synergistic effect with mutant p53 on tumor growth and chromosomal instability--evidence of E2F-1 transcriptional control over hCdt1.

Replication licensing ensures once per cell cycle replication and is essential for genome stability. Overexpression of two key licensing factors, Cdc6 and Cdt1, leads to overreplication and chromosomal instability (CIN) in lower eukaryotes and recently in human cell lines. In this report, we analyzed hCdt1, hCdc6, and hGeminin, the hCdt1 inhibitor expression, in a series of non-small-cell lung carcinomas, and investigated for putative relations with G(1)/S phase regulators, tumor kinetics, and ploidy. This is the first study of these fundamental licensing elements in primary human lung carcinomas. We herein demonstrate elevated levels (more than fourfold) of hCdt1 and hCdc6 in 43% and 50% of neoplasms, respectively, whereas aberrant expression of hGeminin was observed in 49% of cases (underexpression, 12%; overexpression, 37%). hCdt1 expression positively correlated with hCdc6 and E2F-1 levels (P = 0.001 and P = 0.048, respectively). Supportive of the observed link between E2F-1 and hCdt1, we provide evidence that E2F-1 up-regulates the hCdt1 promoter in cultured mammalian cells. Interestingly, hGeminin overexpression was statistically related to increased hCdt1 levels (P = 0.025). Regarding the kinetic and ploidy status of hCdt1- and/or hCdc6-overexpressing tumors, p53-mutant cases exhibited significantly increased tumor growth values (Growth Index; GI) and aneuploidy/CIN compared to those bearing intact p53 (P = 0.008 for GI, P = 0.001 for CIN). The significance of these results was underscored by the fact that the latter parameters were independent of p53 within the hCdt1-hCdc6 normally expressing cases. Cumulatively, the above suggest a synergistic effect between hCdt1-hCdc6 overexpression and mutant-p53 over tumor growth and CIN in non-small-cell lung carcinomas.

Aged↗

PubMed2004

COX-2 inhibition in cancer therapeutics: a field of controversy or a magic bullet?

Carcinogenesis is a multistep process of long-term accumulation of genetic and epigenetic aberrations at the molecular level. Understanding the mechanisms underlying carcinogenesis could further provide insights for rationally designed new therapeutic strategies for cancer prevention and treatment. Epidemiological and experimental evidence supports the preventative effect of non-steroidal anti-inflammatory drugs (NSAIDs) regarding cancer development. NSAIDs inhibit cyclooxygenase (COX) activity, thus blocking the endogenous prostaglandin production. COX-2 is a key isoenzyme in this biochemical cascade and is inducible by various oncogenic stimuli. A large volume of research data has shown that COX-2 is often upregulated in many malignant tumours, rendering it an attractive candidate target for cancer therapeutics. Various possible direct mechanisms for COX-2 implication in carcinogenesis have been suggested, whilst intense interest has recently been focused on COX-2-independent effects of NSAIDs. Several COX-2-selective inhibitors are currently under evaluation in preclinical and clinical studies, either as single agents or in combination with conventional chemotherapy, radiotherapy and other new molecularly-targeted compounds, with promising results. This article critically reviews already published data on COX-2-selective inhibitors that have been tested in cancer clinical trials, highlights ongoing research and considers the future perspectives of this novel class of agents.

Animals↗

PubMed2003

Retinoid-X-receptor alpha (RXRalpha) expression during laryngeal carcinogenesis: detrimental or beneficial event?

RXRalpha is an obligatory heterodimerization partner in many signal transducing pathways. To evaluate RXRalpha expression during laryngeal carcinogenesis, immunohistochemistry was performed on laryngeal epithelial specimens of 154 patients with normal-appearing, hyperplastic, dysplastic laryngeal epithelium and squamous cell carcinoma. RXRalpha up-regulation was detected from the early stages of laryngeal carcinogenesis compared with normal epithelium. Statistical analysis and correlation of the intensity of nuclear immunostaining among the various histologic entities revealed statistically significant results. We pose that RXRalpha overexpression might represent an early protective effect in the process of laryngeal carcinogenesis that might be overwhelmed by an epigenetic disability in forming heterodimers with PPARgamma.

Adult↗

PubMed2003

p53 activates ICAM-1 (CD54) expression in an NF-kappaB-independent manner.

Intercellular adhesion molecule-1 (ICAM-1) is a crucial receptor in the cell-cell interaction, a process central to the reaction to all forms of injury. Its expression is upregulated in response to a variety of inflammatory/immune mediators, including cellular stresses. The NF-kappaB signalling pathway is known to be important for activation of ICAM-1 transcription. Here we demonstrate that ICAM-1 induction represents a new cellular response to p53 activation and that NF-kappaB inhibition does not prevent the effect of p53 on ICAM-1 expression after DNA damage. Induction of ICAM-1 is abolished after treatment with the specific p53 inhibitor pifithrin-alpha and is abrogated in p53-deficient cell lines. Furthermore, we map two functional p53-responsive elements to the introns of the ICAM-1 gene, and show that they confer inducibility to p53 in a fashion similar to other p53 target genes. These results support an NF-kappaB-independent role for p53 in ICAM-1 regulation that may link p53 to ICAM-1 function in various physiological and pathological settings.

Base Sequence↗

PubMed2003

Functional significance of the thyrotropin receptor germline polymorphism D727E.

In a toxic thyroid adenoma we identified a novel somatic mutation that constitutively activates the thyrotropin receptor (TSHR). Two heterozygous point mutations at adjacent nucleotides led to a substitution of alanine with asparagine at codon 593 (A593N) in the fifth transmembrane helix of TSHR. This somatic mutation resided on the same TSHR allele with the germline polymorphism D727E. The functional characteristics of the single TSHR mutants A593N and D727E and of the double mutant A593N/D727E were studied in transiently transfected COS-7 cells. The TSHR mutants A593N and A593N/D727E constitutively activated the cAMP cascade, whereas the D727E mutant did not differ from the wild-type TSHR. Surprisingly, the double mutant's specific constitutive activity was 2.3-fold lower than the A593N mutant. Thus, the polymorphism significantly ameliorates G(alphas) protein activation in the presence of the gain-of-function mutation A593N, although it is functionally inert in the context of the wild-type TSHR.

Adenoma↗