Institute of Cell Biology National Academy of Sciences of Ukraine

Department of Cell Signaling

Head of Department – Oleh Stasyk, PhD, DrSc, senior scientist.

The Department conducts comprehensive research aimed at establishing the molecular signaling mechanisms of the response of tumor cells of different organ origin to the deficiency of individual amino acids and the development of new combined approaches of antitumor metabolic therapy.

Institute of Cell Biology National Academy of Sciences of Ukraine

Department of Cell Signaling

The Department of Cell Signaling conducts research aimed at increasing the efficacy and selectivity of combined antitumor metabolic therapy based on arginine starvation. In particular, the effect of arginine starvation combined with plant analogues of arginine, canavanine and indospicine, as well as mTOR and MAPK inhibitors on the proliferation and viability of diverse human tumor cells, is studied.

Indospicine has been shown for the first time to selectively impair the viability of human colorectal cancer tumor cells during arginine starvation, by integrating into newly synthesized proteins, deregulating the mTOR and MAPK signaling pathways, and causing ER stress and apoptosis. Given that this analogue is not degradated by recombinant human arginase, which is used to achieve deficit of this amino acid in vivo, indospicine is a promising component of combined metabolic therapy. It was also found that inactivation of pro-proliferative ERK and activation of proapoptotic p38 MARK may be one of the causes of antitumor effects of arginine analogues under arginine starvation. Simultaneous impact of canavanine and the autophagy inhibitor chloroquine has been shown to induce apoptotic cell death in SCOV3 ovarian carcinoma cells. It was also found for the first time that knockout of the mTOR TSC2 repressor gene increases the sensitivity of SW480 colorectal carcinoma cells to arginine starvation and sensitizes them to canavanine.

The obtained results are also the basis for studying the effectiveness of combined antitumor therapy based on arginine starvation in experimental animal models.

Thus, the main research topics of the Department are:

1. Development of new approaches to anti-tumor metabolic therapy based on individual amino acid starvation.
2. Study of molecular signaling mechanisms involved in the response of tumor cells to starvation of individual amino acids.
3. Construction of yeast-based producers of recombinant enzymes for metabolic antitumor therapy.
4. Utilization of yeast as an experimental model for the study of malignant transformation and neurodegenerative human diseases.
5. Development of highly selective monoclonal antibodies for biotechnological purposes.

The Department of Cell Signaling also actively cooperates with the Faculty of Biology of Lviv Ivan Franko National University. Thus, during 2020 the Department completed 2 course works of 3rd year students, 3 diploma bachelor theses of 4th year students, 3 course works of 1st year masters, and 1 master theses of 2nd year in the specialty "091 Biology".

Institute of Cell Biology National Academy of Sciences of Ukraine

Department of Cell Signaling

Publications

2008

1. Stasyk O.G., Maidan M., Stasyk O.V., Van Dijck P., Thevelein J.M., Sibirny A.A. Identification of hexose transporter-like sensor HXS1 and functional hexose transporter HXT1 in the methylotrophic yeast Hansenula polymorpha // Eukaryotic Cell. -2008.- V.7, № 4. – P.735-746.
2. Ishchuk O.P., Voronovsky A.Y., Stasyk O.V., Gayda G.Z., Gonchar M.V., Abbas C.A., Sibirny A.A. Improvement of xylose high-temperature fermentation in Hansenula polymorpha due to overexpression of the PDC1 gene coding for pyruvate decarboxylase // FEMS Yeast Research. – 2008. – V.8, № 7. – P.1164-1174.
3. Sybirna N., Brodiak I., Ferents I., Barska M. The effect of L-arginine on the oxidative modification of plasma fibrinogen under experimental diabetes mellitus in rats // Annal. Univers. Mariae Curie-Sklodovska, sectio AA Biologia – 2008. – V. IX,– P. 115-118.

2009

1. Havrylov S., Rzhepetskyy Yu., Malinowska A., Drobot L., Rendowicz M.J. Proteins recruited by SH3 domains of Ruk/CIN85 adaptor identified by LC-MS/MS // Proteome Science.-2009.-Vol. 7, N21.-P. 1-19.
2. O.I. Basaraba, M.L. Barska, Ya.P. Bobak, H.Yu. Shuvayeva, S.M. Marchenko, V. R. Savran, N.A. Volodko, V.L. Buchman, L.B. Drobot. Expression of (RUK/CIN85)/(CD2AP/CMS) family adapter proteins in human breast adenocarcinoma // Clin. and Experim. Potol.-2009- V. 9, № 4. – P. 125-130.
3. Rzhepetskyy Y.А., Svinchuk V.V., Buchman V.L.,Drobot L.B. Comparative analysis of Ruk/CIN85 phosphorylation in rat pheochromocytome cell line PC12 under growth factors stimulation// Clinical and eksperimental pathology. 2009.- V. VIII, №2.- p. 64-67.
4. Brodyak I.V., Zdioruk N.І., Barska M.L., Vovk O.І., Sybirna N.O. Lectincytochemical analysis of mononuclear leukocyte plasmatic membrane sialocontaining glycoprotein of peripheral blood under type 1 diabetes mellitus // Med.Chim. – 2009. – № 4. – P. 76–79 (Ukrainian).
5. Zdioruk M.I., Barska M.L., Brodyak I.V., Vovk O.I. Urbanovych A.M., Sybirna N.O. Influence of wortmannin on aggregation ability of neutrophylic granulocytes under type 1 diabetes mellitus / Studia Biologica.– 2009. –V.3, №2. – P. 133–140 (Ukrainian).

2010

1. Bobak Y.P., Vynnytska B.O., Kurlishchuk Y.V., Sibirny A.A., Stasyk O.V. Cancer cell sensitivity to arginine deprivation in vitro is not determined by endogenous levels of arginine metabolic enzymes // Cell Biol Int.-2010.-V.34 (11).-P.1085–1089.
2. Stadnyk V.V., Izyumovaa L.A., Rzhepetskiy Y.A., Mayor C.Y., Vlizlo V.V. The Antisense Oligonucleotides Decrease Expression of the Cellular Prion // Letters in Drug Design & Discovery.- 2010,-V.7.- P.23-26.
3. Jóźwiak J., Rzhepetskiy Y., Sobczak M., Kocik E., Skórzewski R., Kłopocka W., Rędowicz M.J. Amebin a novel Amoeba Proteus actin-bundling protein inhibits actomyosin ATPase activity and is essential for Amoeba migration // Archives of Biochemistry and Biophysics.- 2010, (published ahead of print).

Tutorials and methodical editions:

1. Chemistry of the Protein: texbook: [for university students] / [ N.О. Sybyrna, М.V. Gonchar, І.V. Brodyak, О.G. Stasyk, М.L. Barska] edited by Prof. N.О. Sybyrna. - Lviv: Ivan Franko Lviv national University. 2010 - pp.393 . Labeled by MES of Ukraine.

2011

1. Vynnytska B.O., Mayevska O.M., Kurlishchuk Y.V., Bobak Y.P., Stasyk O.V. Canavanine augments proapoptotic effects of arginine deprivation in cultured human cancer cells // Anticancer Drugs. – 2011. – V.22 (2). – P. 148 – 157. (IF=2.407) (Scopus)
2. Jozwiak J, Rzhepetskyy Y, Sobczak M, Kocik E, Skorzewski R, Klopocka W, Redowicz MJ. C-terminal fragment of amebin promotes actin filament bundling, inhibits acto-myosin ATPase activity and is essential for amoeba migration // Arch. Biochem. Biophys. – 2011. – V. 506(1). – P. 99-108. (IF=2.935) (Scopus)
3. Nazarko V.Y., Nazarko T.Y., Farre J.C., Stasyk O.V., Warnecke D., Ulaszewski S., Cregg J.M., Sibirny A.A., Subramani S. Atg35, a micropexophagy-specific protein that regulates micropexophagic apparatus formation in Pichia pastoris // Autophagy. – 2011. – V. 7(4). – P. 375-385. (IF=7.453) (Scopus)
4. Sybirna N., Brodyak I., Zdioruk M., Barska M. Sialic acid-containing glycoproteins are the marker molecules that determine the leukocyte functional state under diabetes mellitus // Sepsis. 2011. – V. 4(1) – P. 47-55. (Google Scholar)
5. Стасюк Н.Є., Карпʼяк В.В., Гайда Г.З., Гайда А.В., Стасик О.В., Гончар М.В. Синтез афінних сорбентів для виділення рекомбінантної аргінази і людини із генетично модифікованих дріжджів Нansenula polymorpha //Праці НТШ, Хем. Біохем. – 2011. – Т. 28. – С.139-149. (Google Scholar)
6. O.I. Chen, L.S. Lyniv, N.I. Igumentseva, M.L. Barska, N.O. Effect of nitric oxide donor on viability of human leukemic cells upon arginine deprivation // Studia Biologica. – 2011. – V. 5, N 2. – P. 17–28. (Google Scholar)
7. Сибірна Н.О., Здіорук М.І., Бродяк І.В., Барська М.Л., Вовк О.І. Активація фосфатидилінозитол-3′-кіназного шляху лектиніндукованим сигналом через сіаловмісні глікопротеїни мембран лейкоцитів при цукровому діабеті 1-го типу // Укр. біохім. Журнал. – 2011. – Т. 83. - № 5. – С. 22-31. (Google Scholar)
8. Vovk O.I., Rzhepetskyy Y.A., Pereverzeva H.G., Stasyk O.V. Expression of recombinant human argininosuccinate synthetase in Escherichia coli // Біологічні Студії / Studia Biologica. – 2011. – Том 5. - №3 - С. 19–28. (Google Scholar)
9. Стасюк Н., Гайда Г., Гайда А., Стасик О., Карпʼяк В., Гончар М. Синтез афінних сорбентів для очищення аргінази І людини із рекомбінантних дріжджів Нansenula polymorpha // Праці НТШ, Хем. Біохем. – 2011. – Т.28. – С.139-149. (Google Scholar)
10. Стасик О. Г., Стасик О. В. Селективна деградація пероксисом у дріжджів Hansenula polymorpha потребує стеролглюкозилтрансферазу Atg26 // Біологічні студії. – 2011. – Т.5, №2. – С. 93-104. (Google Scholar)
11. Ю.В. Курліщук, Б.О. Винницька-Мироновська, Я.П. Бобак, О.В. Стасик (2011) Вплив метаболітів аргініну на життєздатність людських пухлинних клітин за умов дефіциту цієї амінокислоти in vitro. Біологічні студії. – 2011. - Т.5, №2. - С. 5-16. (Google Scholar)

2012

1. Vynnytska-Myronovska B., Bobak Y., Garbe Y., Dittfeld C., Stasyk O., Kunz-Schughart L.A. Single amino acid arginine starvation efficiently sensitizes cancer cells to canavanine treatment and irradiation // Int. J. Cancer. – 2012. – V. 130, № 9. – P. 2164 – 2175 (IF=6.198). (Scopus)
2. Zakalskiy AE, Zakalska OM, Rzhepetskyy YA, Potocka N, Stasyk OV, Horak D, Gonchar MV. Overexpression of (His)(6)-tagged human arginase I in Saccharomyces cerevisiae and enzyme purification using metal affinity chromatography // Protein Expr Purif. -2012.- 81(1). –P. 63-68. (IF=1.429) (Scopus)
3. Samoylenko A., Vynnytska-Myronovska B., Byts N., Kozlova N., Basaraba O., Pasichnyk H., Palyvoda K., Bobak Ya., Barska M., Mayevska O., Rzhepetskyy Y., Shuvayeva H., Lyzogubov V., Usenko V., Savran V., Volodko N., Buchman V.L., Kietzmann T., Drobot L. Increased levels of the HER1 adaptor protein Rukl/CIN85 contribute to breast cancer malignancy // Carcinogenesis. - 2012.- Vol. 33, №10.-P. 1976-1984 (IF=5.635) (Scopus)
4. Сибірна Н.О., Бродяк І.В., Барська М.Л., Вовк О.І. Участь ензиму фосфатидилінозитол-3ʼ-кінази у процесах сприйняття і передачі сигналів через галактозилумісні глікопротеїнові рецептори сегментоядерних лейкоцитів при цукровому діабеті 1 типу // Фізіологічний журнал. – 2012. - T. 58, №6. - С. 9-22. (Google Scholar)
5. O. Chen, M. Barska, N. Sybirna, O. Stasyk. Development and evaluation of HPLC method for arginine assay in biological samples // Вісник Львівського університету. Серія біологічна. – 2012. – Том 60. –С. 73–82. (Google Scholar)

2013

1. Krasovska O.S., Stasyk O.V., Sibirny A.A. Stable overproducer of hepatitis B surface antigen in the methylotrophic yeast Hansenula polymorpha due to multiple integration of heterologous auxotrophic selective markers and defect in peroxisome biogenesis // Appl. Microbiol. Biotechnol. – 2013. – Vol. 97, No. 23. – P. 9969-9979 (ІF=3.811) (Scopus)
2. Vynnytska-Myronovska B., Kurlishchuk Y., Bobak Y., Dittfeld C., Kunz-Schughart L.A., Stasyk O. Three–dimensional environment renders cancer cells profoundly less susceptible to a single amino acid starvation // Amino Acids. – 2013. – V. 45, № 5. – P. 1221-1230 (IF=3.653) (Scopus)
3. Chen O., Kavalets B., Barska M., Lyniv L., Vovk O., Sybirna N. Stasyk O. Effect of combinational arginase and canavanine treatment on normal human peripheral blood lymphocytes in vitro // Curr. Issues Pharm. Med. Sci. – 2013 - Vol. 26, No. 4, Pages 385–389. (Scopus)
4. Sybirna N.O., Brodyak I.V., Barska M.L., Vovk O.I. Participation of Phosphatidylinositol-3ʼ-kinase in Perception and Signal Transduction through Galactosyl-Containing Glycoprotein Receptors of Segmented Leukocytes under Type 1 Diabetes Mellitus // International Journal of Physiology and Pathophysiology. – 2013– V.4, №3. – P. 213-230. (IF=0.150) (Google Scholar)

2014

1. Petryk N., Zhou Y.F., Sybirna K., Mucchielli M.H., Guiard B., Bao W.G., Stasyk O.V., Stasyk O.G., Krasovska O.S., Budin K., Reymond N., Imbeaud S., Coudouel S., Delacroix H., Sibirny A., Bolotin-Fukuhara M. Functional study of the Hap4-like genes suggests that the key regulators of carbon metabolism HAP4 and oxidative stress response YAP1 in yeast diverged from a common ancestor. PLoS One. 2014 Dec 5;9(12):e112263. doi: 10.1371/journal.pone.0112263. eCollection 2014. (IF=3.234) (Scopus)
2. Shuvayeva Galyna, Bobak Yaroslav, Igumentseva Natalia, Titone Rossella, Morani Federica, Stasyk Oleh, Isidoro Ciro. Single Amino Acid Arginine Deprivation Triggers Prosurvival Autophagic Response in Ovarian Carcinoma SKOV3 // BioMed Research International. Volume 2014 , Article ID 505041, 10 pages, (IF=1.579) (Scopus)
3. Mathias Stiller, Martyna Molak, Stefan Prost, Gernot Rabeder, Gennady Baryshnikov, Wilfried Rosendahl, Susanne Münzel, Hervé Bocherens, Aurora Grandal-dʼAnglade, Brigitte Hilpert, Mietje Germonpré, Oleh Stasyk, Ron Pinhasi, Andrea Tintori, Nadin Rohland, Elmira Mohandesan, Simon Y.W. Ho, Michael Hofreiter, Michael Knapp Mitochondrial DNA diversity and evolution of the Pleistocene cave bear complex // Quaternary International. – 2014. – 339–340:224-231 (IF=2.062) (Scopus)
4. Vynnytska-Myronovska B.O., Bobak Y.P., Pasichnyk G.V., Igumentseva N.I., Samoylenko A.A., Drobot L.B.. Multiple molecular forms of adaptor protein Ruk/CIN85 specifically associate with different subcellular compartments in human breast adenocarcinoma MCF-7 cells. Ukr Biochem J. 2014 Sep-Oct;86(5):102-10. (Google Scholar)
5. Denega I.O., Klymyshyn N.I., Sybirna N.O., Stasyk О.V., Stasyk О.G.. Modeling of molecular processes underlying Parkinsonʼs disease in cells of methylotrophic yeast Hansenula polymorpha // Біологічні студії/Studia Biologica. – 2014. – Т. 8, № 12. – C. 5–16. (Google Scholar)