Assistant Professor, Biochemistry and Molecular Biology
Phone: 402-559-1794 (Office)
M.D., Crimean State Medical University, Simferopol, Ukraine, 1995
Ph.D., Donetsk National Medical University, Donetsk, Ukraine, 2008
Primary Research/Clinical Interests/Expertise:
Mechanism of Golgi alteration in advanced prostate cancer: focus on aberrant glycosylation.
The role for non-muscle Myosin IIA in alcohol-induced Golgi fragmentation.
The Golgi apparatus is a dynamic posttranslational modification and sorting station for secreted and membrane-bound proteins. It undergoes constant remodeling under normal physiological conditions and significant morphological changes in response to stress. We have found that motor protein, non-muscle Myosin IIA (NMIIA), is responsible for Golgi remodeling and stress/malignancy-induced Golgi fragmentation. Importantly, fragmentation of the Golgi is mediated by interaction Golgi glycosyltransferases to NMIIA and accompanied by proteasomal degradation of glycosyltransferases. Further, Golgi fragmentation and altered glycosylation have been reported in prostate cancer, but the significance of their link is only beginning to be understood. We found that anterograde ER-to-Golgi trafficking of glycosyltransferases is COPII- and COPI-independent process and have uncovered glycosyltransferase-specific Golgi targeting mechanisms.
We detected that the transport vesicles carrying a Core-1, and Core-2 O-glycosylation enzymes (C1GalT1 and C2GnT-M, respectively) are segregated and utilize different Golgi matrix proteins (golgins) for Golgi targeting. C1GalT1 uses GM130-GRASP65 or GM130-Giantin, while C2GnT-M or C2GnT-L employs Giantin exclusively. Next, we extended this observation to explain the phenomenon that prostate cancer progression is associated with up-regulation of sialyl-T antigen produced by β-galactoside α-2,3-sialyltransferase-1 (ST3Gal1). We found that prostate cancer progression is accompanied by Golgi fragmentation and ER-relocation of Core-2 enzymes, while ST3Gal1 was still found in the Golgi. We observed that failure of Giantin monomers to be phosphorylated and dimerized prevents Golgi from forming compact morphology and Core-2 enzymes from targeting the Golgi. On the other hand, ST3Gal1 reaches the Golgi by an alternate site, GM130-GRASP65.
The current research focuses on the role for alcohol in pathogenesis and progression of prostate cancer. Briefly, malignant transformation is accompanied by the enhanced interaction of Rab6a and NMIIA followed by formation of complex NMIIA-glycosyltransferase, which, in turn, provides the force for the disruption of Golgi membranes. Meantime, ethanol metabolism results in the defective Giantin structure and downregulation of its dimerization, thereby facilitating Golgi membranes disintegration and blocking the Core-2 enzymes delievery to the Golgi. On the other hand, ST3Gal1 reaches the Golgi by an alternate site, GM130-GRASP65. Interestingly, inhibition or knockdown of NMIIA frees up Rab6a GTPase to promote phosphorylation of Giantin by polo-like kinase 3 (PLK3), which is followed by dimerization of Giantin assisted by protein disulfide isomerase A3 (PDIA3), and restoration of compact Golgi morphology and targeting of Core-2 enzymes. Finally, the Golgi relocation of Core-2 enzymes in androgen-refractory cells results in their increased susceptibility to galectin-1-induced apoptosis by replacing sialyl-T antigen with polylactosamine. Although sialic acids play a vital role in many biologic processes, hypersialylation in particular has been shown to contribute to cancer cell progression and metastasis. This study demonstrates the importance of Golgi morphology in the regulation of O-glycosylation, and provides NMIIA inhibition as the strategy for anticancer therapy.
Pictured: Sonia Manca, PhD; Armen Petrosyan, MD, PhD; Cole Frisbie, BSc.
Selected Recent Publications:
Casey C, Bhat G, Holzapfel MS, Petrosyan A. (2016) Study of ethanol-induced Golgi disorganization reveals the potential mechanism of alcohol-impaired N-glycosylation. Alcoholism, clinical and experimental research. 40(12):2573 2590.
Petrosyan A, Casey CA, Cheng PW. (2016) The role of Rab6a and phosphorylation of non-muscle myosin IIA tailpiece in alcohol-induced Golgi disorganization. Scientific Reports. 6, 31962; doi: 10.1038/srep31962 (2016). http://www.nature.com/articles/srep31962
Kubyshkin A, Chegodar D, Katsev A, Petrosyan A, Krivorutchenko Y, Postnikova O. (2016) Antimicrobial Effects of Silver Nanoparticles Stabilized in Solution by Sodium Alginate. Biochem Mol Biol J. Vol 2 (2):13. DOI: 10.21767/2471-8084.100022. http://biochem-molbio.imedpub.com/antimicrobial-effects-of-silver-nanoparticles-stabilized-in-solution-by-sodium-alginate.php?aid=11323
Petrosyan A, Cheng PW, Clemens DL, Casey CA. (2015) Downregulation of the small GTPase Sar1a: a key event underlying alcohol-induced Golgi fragmentation in hepatocytes. Scientific Reports. 2015 Nov 26;5:17127. doi: 10.1038/srep17127.http://www.nature.com/articles/srep17127
Petrosyan A. Onco-Golgi: is fragmentation a gate to cancer progression? Biochem & Mol Biol Journal. November, 2015 (Vol 1:6). http://biochem-molbio.imedpub.com/oncogolgi-is-fragmentation-a-gate-to-cancer-progression.php?aid=7530
Cheng PW, Casey CA, Petrosyan A. A study of alcohol-induced Golgi fragmentation in hepatocytes reveals an emerging role for the small GTPase Sar1a in maintaining Golgi integrity and giantin-dependent targeting of glycosyltransferases. 2015 ASCB Annual Meeting abstracts. Mol. Biol. Cell 2015 26:25 4523; doi:10.1091/mbc.E15-09-0674.
Petrosyan A, Ali MF, Cheng PW. (2015) Keratin 1 plays a critical role in Golgi localization of Core 2 N-acetylglucosaminyltransferase M via interaction with its cytoplasmic tail. The Journal of Biological Chemistry. Jan 20. doi: 10.1074/jbc.M114.618702.
Petrosyan A, Holzapfel MS, Muirhead DE, Cheng PW. (2014) Restoration of Compact Golgi Morphology in Advanced Prostate Cancer Enhances Susceptibility to Galectin-1-induced Apoptosis by Modifying Mucin O-glycan Synthesis. Molecular Cancer Research. 12(12):1704-1716.
Petrosyan A, Cheng PW. (2014) Golgi fragmentation induced by heat shock or inhibition of heat shock proteins is mediated by non-muscle myosin IIA via its interaction with glycosyltransferases. Cell Stress and Chaperones 19 (2):241-254.
Petrosyan A, Cheng PW. (2013) A non-enzymatic function of Golgi glycosyltransferases: Mediation of Golgi fragmentation by interaction with non-muscle myosin IIA. Glycobiology 23(6):690-708.
Petrosyan A, Ali MF, Cheng PW. (2012) Glycosyltransferase-specific Golgi targeting mechanisms. Journal of Biological Chemistry 287(45):37621-37627.
Ali MF, Chachadi VB, Petrosyan A, Cheng PW. (2012) Golgi phosphoprotein 3 determines cell binding properties under dynamic flow by controlling Golgi localization of Core 2 N-acetylglucosaminyltransferase. Journal of Biological Chemistry 287(47):39564-39577.
Petrosyan A, Ali MF, Verma SK, Cheng H, Cheng PW. (2012) Non-muscle myosin IIA involvement in the Golgi-to-ER transport of glycosyltransferase by binding to its cytoplasmic tail. The International Journal of Biochemistry & Cell Biology. 44(7):1153-1165.
Petrosyan A. (2007) Serum activity of proteinases and their inhibitors, glycosylation of immunoglobulin’s G and their resistance to proteolytic cleavage by trypsin in patients with gastric cancer. Ukrainskii Medichnii Almanakh 10(5):138-142.
Petrosyan A. (2007) Serum IgG-paraproteins glycosylation and activity of proteinases and inhibitors of proteinases in patients with multiple myeloma. Tavricheskiy Mediko-Biologicheskiy Vestnik 10(4):194-201.
Petrosyan A, Kharchenko V. (2006) Activity of blood serum proteinases and inhibitors of proteinases as an index of gastric cancer patient’s severity. Oncologiya 9(4):303-306. http://www.oncology.kiev.ua/
Petrosyan A. (2006) Study of glycosylation of paraproteins and analysis of their electrophoretic mobility in patients with myeloma. Ukrainskii Medichnii Chasopis (5-6):106-112. http://www.umj.com.ua/ article/451/
Iliasov R, Parshkova E, Petrosyan A, Efetov K. (2006) Detection of IgG-paraprotein in the pleural effluent in multiple myeloma. Oncologiya 8(1): 38-42.http://www.oncology.kiev.ua/archiv/28/28_481.php
Petrosyan A, Britan A. (2006) Lectin-enzyme assay as a method of estimation of immunoglobulin’s glycosylation. Ukrainskii Biokhimicheskii Zhurnal 78(4):151-159.
Ushakov A, Petrosyan A, Efetov K. (2005) Glycosylation of serum IgG in patients with myocardial infarction and diabetes mellitus. Tavricheskiy Mediko-Biologicheskiy Vestnik 8(4):150-159.
National Institutes of Health, NIAAA
“Alcohol effect on Golgi morphology and function”