Armen Petrosyan

Assistant Professor, Biochemistry and Molecular Biology

smArmen-Petrosyan,-Ph.D.-7658.jpg

Phone: 402-559-1794 (Office)
402-559-7718 (Lab)
Fax: 402-559-6650
Email

Education/Training:

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.

Figure1The 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.

Figure 2We 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.

Figure 3The 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.

Staff

Labstaff.jpg

Pictured: Sonia Manca, PhD; Armen Petrosyan, MD, PhD; Cole Frisbie, BSc.

Publications:
My Publications

 

Current Grants:

National Institutes of Health, NIAAA
“Alcohol effect on Golgi morphology and function”
09/2014-09/2019
K01AA022979-01

National Institutes of Health
"The role for alcohol-induced Golgi disorganization in the progression of prostate cancer"
8/2019-7/2024
R01AA027242-01