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Zoznam článkov

General Physiology and Biophysics


Volume 36, 2017, No. 5

Content:


 
The role of CYP17A1 in prostate cancer development: structure, function, mechanism of action, genetic variations and its inhibition.
Monika Kmeťová Sivoňová 1), Zuzana Tatarkova, Peter Kaplan, Lucia Lichardusová, Jozef Hatok

1)Department of Medical Biochemistry, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia. sivonova@jfmed.uniba.sk.

Androgens play an important role during the development of both normal prostate epithelium and prostate cancer and variants of genes involved in androgen metabolism may be related to an increased risk of prostate disease. Cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) is a key regulatory enzyme in the steroidogenic pathway; it catalyses both 17α-hydroxylase and 17,20-lyase activities and is essential for the production of both androgens and glucocorticoids. In this review, we focus on the structure and enzymatic activity of CYP17A1 and the mechanism of modulation of CYP17A1 activities. We discuss the relationship between common genetic variations in CYP17A1 gene and prostate cancer risk and the main effects of these variations on the prediction of susceptibility and clinical outcomes of prostate cancer patients. The mechanism of action, the efficacy and the clinical potential of CYP17A1 inhibitors in prostate cancer are also summarized.

How to cite (APA format):
Kmeťová Sivoňová, M, Tatarkova, Z, Kaplan, P, Lichardusová, L, Hatok, J. (2017). The role of CYP17A1 in prostate cancer development: structure, function, mechanism of action, genetic variations and its inhibition. General Physiology and Biophysics, 36(5), 487-499.


 
The role of statins as therapeutic agents in cancer.
Jana Sopková 1), Eva Vidomanová, Ján Strnádel, Henrieta Škovierová, Erika Halašová

1)Department of Medical Biochemistry, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia. evablahovcova@yahoo.com.

Statins are the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. This enzyme catalyzes conversion of HMG-CoA to mevalonate, which are the intermediates in cholesterol biosynthetic pathway. Statins also play an important role in carcinogenesis, because they are able to affect the cancer cell metabolism. Their effect has been observed in several cellular processes, such as angiogenesis, metastasis, apoptosis and cell proliferation. However, these effects are highly dependent on type of cancer and individual statins vary in their antitumor potential. This review summarizes the recent epidemiological evidence and preclinical studies that showed effects of all clinically used statins in vitro and in vivo. We also consider the results of different observational and retrospective studies focused on association among statins and cancer risk which are still under open discussion.

How to cite (APA format):
Sopková, J, Vidomanová, E, Strnádel, J, Škovierová, H, Halašová, E. (2017). The role of statins as therapeutic agents in cancer. General Physiology and Biophysics, 36(5), 501-511.


 
Role of S-adenosylmethionine cycle in carcinogenesis.
Radovan Murín 1), Eva Vidomanová, Bhavani Kowtharapu, Jozef Hatok, Dušan Dobrota

1)Department of Medical Biochemistry, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia. murin@jfmed.uniba.sk.

Alterations in enzymatic activities underlying the cellular capacity to maintain functional S-adenosylmethionine (SAM) cycle are associated with modified levels of its constituents. Since SAM is the most prominent donor of methyl group for sustaining the methylation pattern of macromolecules by methyltransferases, its availability is an essential prerequisite for sustaining the methylation pattern of nucleic acids and proteins. In addition, increased intracellular concentrations of S-adenosylhomocysteine and homocysteine, another two constituents of SAM cycle, exerts an inhibitory effect on the enzymatic activity of methyltranferases. While methylation pattern of DNA and histones is considered as an important regulatory hallmark in epigenetically regulated gene expression, amended methylation of several cellular proteins, including transcription factors, affects their activity and stability. Indeed, varied DNA methylome is a common consequence of disturbed SAM cycle and is linked with molecular changes underlying the transformation of the cells that may underlay the carcinogenesis. Here we summarize the recent evidences about the impact of disturbed SAM cycle on carcinogenesis.

How to cite (APA format):
Murín, R, Vidomanová, E, Kowtharapu, B, Hatok, J, Dobrota, D. (2017). Role of S-adenosylmethionine cycle in carcinogenesis. General Physiology and Biophysics, 36(5), 513-520.


 
DNA methylation as mechanism of apoptotic resistance development in endometrial cancer patients.
Veronika Fialkova 1), Eva Vidomanová, Tomas Balharek, Juraj Marcinek, Erik Kudela, Sandra Hanysova, Jozef Visnovsky, Dušan Dobrota, Jozef Hatok

1)Department of Medical Biochemistry, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia. hatok@jfmed.uniba.sk.

DNA methylation is a significant epigenetic modification which plays a key role in regulation of gene expression and influences functional changes in endometrial tissue. Aberrant DNA methylation changes result in deregulation of important apoptotic proteins during endometrial carcinogenesis and apoptosis resistance development. Evading apoptosis is still a major problem in the successful treatment of endometrial cancer patients. The aim of our study was to examine the promoter DNA methylation changes in 22 apoptosis-associated genes in endometrioid endometrial cancer patients, precancerous lesions and healthy tissue from various normal menstrual cycle phases using a unique pre-designed methylation platform. We observed as the first a significant difference in promoter DNA methylation status in genes: BCL2L11 (p < 0.001), CIDEB (p < 0.03) and GADD45A (p < 0.05) during endometrial carcinogenesis and BIK gene (p < 0.03) in different phases of normal menstrual cycle. The results of our study indicate that deregulation of mitochondrial apoptotic pathway can considerably contributes to the apoptosis resistance development and may be helpful in identifying of new potent biomarkers in endometrial cancer.

How to cite (APA format):
Fialkova, V, Vidomanová, E, Balharek, T, Marcinek, J, Kudela, E, Hanysova, S, Visnovsky, J, Dobrota, D, Hatok, J. (2017). DNA methylation as mechanism of apoptotic resistance development in endometrial cancer patients. General Physiology and Biophysics, 36(5), 521-529.


 
Proton MR spectroscopic imaging of human glioblastomas at 1.5 Tesla.
Petra Hnilicová 1), Romana Richterová, Ema Kantorová, Michal Bittšanský, Eva Baranovičová, Dušan Dobrota

1)Division of Neurosciences at Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia. dusan.dobrota@jfmed.uniba.sk.

In this study we evaluated clinical feasibility of proton magnetic resonance spectroscopy metabolite mapping (1H MRSI) by using 1.5 Tesla MR-scanner in 10 patients with high-grade glioblastoma. In vivo 1H MRSI performed with a relatively short scan time of 20 minutes enabled to obtain comprehensive information about metabolic changes in glioblastoma and adjacent tissues namely in the peritumoral edema, in the middle and solid part of the tumor, and in the normal-appearing brain tissue. Spectroscopically it was possible to identify initiation of neuronal cell death in the solid tumorous tissue via decreased N-acetyl-aspartate to creatine ratio (↓ tNAA/tCr) and expanding carcinogenesis reflected in elevated choline ratios (↑ tCho/tCr and tCho/tNAA). We showed also the central necrosis of glioblastoma accompanied by the tissue hypoxia, which were apparent as increased lactate and lipids ratios (↑ Lac/tCr and lip/Lac). Metabolic changes were noticeable also in the peritumoral area, showing the glioblastoma infiltration into the surrounding tissues. In intracranial tumors, 1H MRSI performed on 1.5 Tesla field strength was sufficient to provide information about the stage of carcinogenesis, tumor expansion or necrotization and thus it could be considered as a useful diagnostic tool in oncology.

How to cite (APA format):
Hnilicová, P, Richterová, R, Kantorová, E, Bittšanský, M, Baranovičová, E, Dobrota, D. (2017). Proton MR spectroscopic imaging of human glioblastomas at 1.5 Tesla. General Physiology and Biophysics, 36(5), 531-537.


 
Cyclin-dependent kinase 2 inhibitor SU9516 increases sensitivity of colorectal carcinoma cells Caco-2 but not HT29 to BH3 mimetic ABT-737.
Andrea Štefaniková 1), Katarína Klačanová, Ivana Pilchová, Jozef Hatok, Peter Racay

1)1 Department of Medical Biochemistry Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia. racay@jfmed.uniba.sk.

Colorectal carcinoma (CRC) that represents one of the major causes for cancer-related death in humans is often associated with over-expression of anti-apoptotic proteins of Bcl-2 family. The aim of presented study was to determine the effect of ABT-737 inhibitor of anti-apoptotic proteins Bcl-2, Bcl-XL and Bcl-w as well as cyclin-dependent kinase 2 (CDK2) inhibitor SU9516 alone and in combination with ABT-737 on survival of colorectal cell lines HT29 and Caco-2. We have shown that both Caco-2 and HT29 cells that are relatively resistant to ABT-737 are also partially sensitive to SU9516, which increased sensitivity of Caco-2 but not HT29 cells to ABT-737. Increased sensitivity of Caco-2 cells to ABT-737 after addition of SU9516 correlated well with SU9516-induced decrease of Mcl-1 expression while we have not observed downregulation of Mcl-1 after the treatment of HT29 cells with SU9516. Instead of this, we have shown that treatment of HT29 cells with SU9516 is associated with decreased expression of tumour suppressor protein p53. Our findings provide a rationale for clinical use of Bcl-2 family inhibitors in combination with CDK2 inhibitors for treatment of Mcl-1-dependent colorectal tumours associated with expression of Bcl-2, Bcl-XL and Bcl-w proteins. In addition, we have shown potential of CDK2 inhibitors for treatment of tumours expressing R273H mutant p53.

How to cite (APA format):
Štefaniková, A, Klačanová, K, Pilchová, I, Hatok, J, Racay, P. (2017). Cyclin-dependent kinase 2 inhibitor SU9516 increases sensitivity of colorectal carcinoma cells Caco-2 but not HT29 to BH3 mimetic ABT-737. General Physiology and Biophysics, 36(5), 539-547.


 
Testosterone as a prospective predictor of pathological Gleason score and pathological stage in prostate cancer.
Henrieta Drobková 1), Jana Jurečeková, Marián Grendár, Ján Kliment, Erika Halašová

1)Department of Urology, Jessenius Faculty of Medicine in Martin and University Hospital Martin, Comenius University in Bratislava, Martin, Slovakia. henrieta.drobkova@gmail.com.

The aim of the study was to assess the relationship between preoperative circulating levels of total serum testosterone and pathological Gleason score and pathological stage in prostate cancer patients who underwent radical retropubic prostatectomy. The levels of total serum testosterone were measured in the morning just before surgery in a group of 201 prostate cancer patients. Multinomial logistic regression models were used to model the association between total preoperative testosterone (individually or in combination with other preoperative predictors such as age, PSA, clinical stage and biopsy Gleason score) and pathological Gleason score, pathological stage in prostate cancer patients. The association between age and total testosterone was modelled by robust regression. The total serum testosterone, in combination with other prognostic factors (age, PSA, clinical stage and biopsy Gleason score) in models, was not statistically significant predictor of pathological Gleason score and pathological stage. The highly significant relationship between age and preoperative total testosterone was observed (p = 0). In prostate cancer patients, the level of total serum testosterone increased with age. In conclusion, total testosterone is not a statistically significant predictive factor for pathological Gleason score and pathological stage.

How to cite (APA format):
Drobková, H, Jurečeková, J, Grendár, M, Kliment, J, Halašová, E. (2017). Testosterone as a prospective predictor of pathological Gleason score and pathological stage in prostate cancer. General Physiology and Biophysics, 36(5), 549-556.


 
DPYD genotype and haplotype analysis and colorectal cancer susceptibility in a case-control study from Slovakia .
Tatiana Matáková 1), Erika Halašová, Henrieta Škovierová, Anton Dzian, Dušan Dobrota, Maria Skerenova

1)Department of Molecular Medicine, Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia. molbiol@mfn.sk.

Dihydropyrimidine dehydrogenase (DPD) acts as the first-step enzyme catabolizing pyrimidines in vivo. DPYD gene mutations interfere with the breakdown of uracil and thymine. Genetic variations of DPYD can cause an enzyme deficiency state, which results in severe toxicity or other adverse side effects such as DNA damage or RNA damage caused by imbalance of the nucleotide pool. Our case-control study investigates the possible association between seven DPYD gene polymophisms (rs1801267, rs72547602, rs1801160, rs3918290, rs1801159, rs1801158, rs1801265) and risk of colorectal cancer (CRC). The association analysis for DPD was performed on 273 CRC patients and 187 healthy controls. There is significant allele association of SNP rs1801160 with colorectal cancer (p = 0.003, OR = 3.264, 95% CI = 1.425–7.475) in present analysis. Haplotype analysis of four DPYD polymorphisms showed significant difference in the distribution „IISt“ haplotype between cases and controls. In comparison to the most common haplotype (VISt), the „IISt“ haplotype was associated with increased risk for CRC (p = 0.038, OR = 2.733, 95% CI = 1.019–7.326). The present study suggests that the SNP rs1801160 and the „IISt“ haplotype in the DPYD gene may also have a role in colorectal cancer risk.

How to cite (APA format):
Matáková, T, Halašová, E, Škovierová, H, Dzian, A, Dobrota, D, Skerenova, M. (2017). DPYD genotype and haplotype analysis and colorectal cancer susceptibility in a case-control study from Slovakia . General Physiology and Biophysics, 36(5), 557-563.


 
Association of single nucleotide polymorphisms in FGF-RAS/MAP signalling cascade with breast cancer susceptibility.
Zuzana Dankova 1), Pavol Zubor, Marián Grendár, Andrea Kapinova, Katarina Zelinova, Mariana Jagelkova, Alexandra Gondova, Karol Dokus, Michal Kalman, Zora Lasabova, Jan Danko

1)Division of Oncology, Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Slovakia. dankova@jfmed.uniba.sk.

The fibroblast growth factor receptors (FGFRs) and Ras/mitogen activated protein (RAS/MAP) signalling cascades are the main molecular pathways involved in breast carcinogenesis. This study aims to determine the association between FGF10 (rs4415084 C>T), FGFR2 (rs2981582 C>T) and MAP3K1 (rs889312 A>C) gene polymorphisms and breast cancer, to analyse the discriminative ability of each SNP and to test the accuracy of the predictive breast cancer risk model which includes all SNPs. We conducted a case-control study of 170 women (57.06 ± 11.60 years) with histologically confirmed breast cancer and 146 controls (50.24 ± 10.69 years). High resolution melting (HRM) method with Sanger sequencing validation was used in analyses. We have revealed significant association of FGFR2 and MAP3K1 polymorphisms with breast cancer. The odds ratio of FGFR2 T allele was 1.897 (95% CI 1.231–2.936, p = 0.004) and MAP3K1 C allele 1.804 (95% CI 1.151–2.845, p = 0.012). FGFR2 polymorphism achieved the best discriminative ability (41.95%). The Random Forest algorithm selected FGFR2, MAP3K1 and age as important breast cancer predictors. The accuracy of this prediction model approached moderate accuracy (70%), with 35.9% sensitivity and 88.6% specificity.

How to cite (APA format):
Dankova, Z, Zubor, P, Grendár, M, Kapinova, A, Zelinova, K, Jagelkova, M, Gondova, A, Dokus, K, Kalman, M, Lasabova, Z, Danko, J. (2017). Association of single nucleotide polymorphisms in FGF-RAS/MAP signalling cascade with breast cancer susceptibility. General Physiology and Biophysics, 36(5), 565-572.