Laboratory of Protein Biosynthesis

CONTACTS

(499) 246-50-72

RESEARCH

The major research interests of the laboratory for years are focused on the biosynthesis and role of extracellular matrix proteins and matrix-specific cell-surface receptors, integrins, in oncogenesis. The key cellular functions, modifications of which underlie tumor growth - proliferation, apoptosis, aging,  invasion, and drug resistance - were the subject of investigations. In studies of the 90s, the priority data were obtained, which showed that cell transformation is accompanied by a significant reduction in intracellular degradation and secretion of collagen proteins. At the same time, normal cells produce and secrete heterotrimeric forms of collagen, while transformed cells synthesize both heterotrimeric and homotrimeric forms. These results highlighted the role of post-translational modifications in reducing the total production of extracellular matrix proteins, observed upon oncogenic transformation.  In subsequent studies, performed in models of intestinal carcinoma cell lines, we have shown for the first time that the survival of tumor cells in the absence of their binding to the matrix proteins is ​​associated with a decrease in the expression of integrin alpha v/beta-3, a multifunctional receptor involved in regulating the basic cell behavioral reactions. These results indicate that the functions of integrin receptors are ambiguous and they can stimulate multidirectional reactions in tumor cells of different types, both contributing to and blocking the development of tumor phenotype.   The impact of integrin-induced signaling pathways in tumor invasion and metastasis was investigated in lines of human breast carcinoma cells. It appeared that blocking the signals initiated by the fibronectin receptor VLA-5 in carcinoma cells leads to a drastic inhibition of cell invasion in vitro and reduces expression and secretion of a matrix-specific metalloproteinases MMP-2, known to strongly contribute to tumor cell invasion and metastasis.  It was found that VLA5-generated signals are transduced by recruiting the key signal mediators - protein kinases PI-3K, Akt, and Erk. Further, we demonstrated for the first time that integrin VLA-5 forms complexes on the cell surface with MMP-2, thereby “pulling together” the enzyme with its substrate, matrix proteins, thus contributing to  degradation of matrix and enhancing cell invasion. These results, which are priorities, indicate that the VLA-5 receptor controls the invasion of breast carcinoma cells both by stimulating the expression of MMP-2 collagenase through signal chains and by “recruiting” this protease to the cell surface. These results, which are of a priority, indicate that the VLA-5 receptor controls the invasion of breast carcinoma cells employing a double mechanism: by stimulating the expression of MMP-2 collagenase through a signal pathway, and by recruiting this metalloprotease to the cell surface. In recent years, the laboratory has been studying the specific signaling mechanisms that mediate the impact of individual integrins on tumor progression and the acquisition of drug resistance by tumor cells. Of these studies, an intriguing is finding that VLA-5 receptor enhances the resistance of breast carcinoma cells by suppressing the activity of protein kinase Erk. This observation is not in line with a number of publications that demonstrated that the key function of Erk is to protect tumor cells from different stresses, including those arising from drug treatments. Thus, we demonstrated, on the one hand, the unusual, “non-canonical” function of the Erk protein kinase and, on the other hand, the ability of tumor cells to resist stress impacts via integrin-initiated non-canonical signaling pathways. We found non-canonical functions in another key mediator involved in transmitting integrin-initiated signals, Akt protein kinase, when studying the role of a collagen-specific integrin VLA-2 in the invasive activity of human melanoma cells. This receptor was shown to promote the invasion of melanoma cells by a mechanism based on suppressing the activity of Akt1, which is one of three isoforms of Akt kinase.  

The non-canonical functions of signaling protein kinases are of particular interest in the context of tumor chemotherapy. The mechanisms of almost all currently available targeted antitumor drugs are based on suppressing the activity of individual members of the signaling cascades maintaining the transformed phenotypes. Therefore, the identification of previously unknown functions of signaling kinases is important for the curation of cancer patients. Akt and Erk kinases are central players in the majority of these pathways. For example, Akt inhibitor perifosine demonstrated efficacy in patients with advanced renal cell carcinoma and in ovarian cancer and endometrial cancer patients. A clearcut therapeutic effect was documented in renal cell carcinoma patients treated with Erk inhibitor sorafenib. Obviously, under conditions of  non-canonical, "inversed", activities of these kinases their inhibitors may cause the opposite effects. Thus, it is important to consider all individual functions of an anticancer target in a specific type of cancer.

The laboratory of protein biosynthesis has the equipment and facility that provide further investigations in the fields described above. Researches  are based on methods and approaches that meet the current level of molecular and cellular biology: vast employing the cell culture models of different tumor types; various kinds of microscopy, cytofluorimetry, electrophoresis and enzyme immunoassay of nucleic acids and proteins, PCR, modifications of cell behavior by up- and down-regulation of gene expression, etc.

 

PROJECTS

  • The implication of integrin-dependent signal pathways in oncogenesis. Grant provided by the Russian Fund for Basic Research, 2017-2019. Priority data have been obtained showing that different integrins control various manifestations of tumor progression through signaling pathways specific to individal integrins. 
  • The implication of integrin-dependent signal pathways in the drug resistance  of tumor cells. Grant provided by the Russian Fund for Basic Research 2015-2017. The data  obtained demonstrate for the first time that integrin-dependent stimulating drug resistance of tumor cells may be based on non-canonical activity of protein kinase Erk
  • Investigation of tumor cell resistance to anchorage-dependent apoptosis: role of signaling functions of integrins. Grant provided by the Russian Fund for Basic Research, 2014-2016. Results obtained showed for the first time that implication of integrins in tumor progression occurs through mechanisms based on the noncanonical activity of the Akt family of proteinkinases