Chekhonin V.P., Baklaushev V., Gurina O., Grinenko N., Yusubalieva G., Ryabinina A.
Binary immunoliposomal system directed to Cx43-positive glioma cells
Drug Delivery Technology, Mart 2010, v.10, N 2, p. 42-47
INTRODUCTION
Connexin-43 (Cx43) is the main structural component of gap junctions between astrocytes in the nervous tissue.1 With its four transmembrane domains, Cx43 forms hexameric connexons that allow opening and closing of the transmembrane channel via phosphorylation and dephosphorylation of Cx43 C-terminals.2 Using two extracellular fragments of Cx43 (Е1 and Е2), hemichannels of neighboring cells form a complete gap junction joining cytoplasmas of those cells. Such channels facilitate ionic homeostasis and cell volume maintenance as well as transfer of several intercellular signals, which regulate proliferation, differentiation, apoptosis, adhesion, and migration of embryonic cells during ontogenesis. Of great interest is the participation of Cx43 in the development of invasive gliomas; however, functions of this protein in glioma cell invasion remain not fully understood. For instance, it has been shown that biosynthesis of this protein decreases in high-grade gliomas.8-10 At the same time, some researchers found an increase in Cx43 levels in tumor tissue, eg, in neoplastic endotheliocytes.6 They also revealed an activating influence of Cx43 on invasion of human multiform glioblastoma and its rat equivalent, experimental C6 glioma. Tumor-suppressive effect of Cx43 was supposed to be the result of its interaction with a soluble proliferation inhibitor, CCN3 (NOV). However, further research conducted by the same group has shown that Cx43 expression may also be accompanied by an increased production of a protein related to CCN3, CCN1 (Cyr61), which conversely, activates glioma cells proliferation and migration.12 As a possible result, Cx43-positive cells of the C6-glioma possess a higher migration ability than Cx43-negative ones.
A possible reason for controversial influence of Cx43 on the invasion of high-grade gliomas may be differently directed changes in the expression of Cx43 in glioma cells and in surrounding reactive astrocytes, as it is the case with GFAP, another astroglial marker. It is assumed that Cx43-positive astrocytes precisely play a specific role in active glioma invasion by forming heterological gap junctions with glioma cells.4 It was recently shown that Cx43-positive cells are more resistant to oxidative stress as well as to several other damaging factors. The latter observation makes Cx43 research attractive within the framework of the concept of glioma cell populations resistant to chemo and radiation therapy. Thus, clarifying the actual Cx43 role in glioma invasion becomes a challenging, yet promising, task.
In our previous research, we have obtained monoclonal antibodies (MAb) to the recombinant extracellular E2 domain, which interacted with the Cx43 in native conformation. The present work was designed to evaluate the Cx43-positive cell selectivity of a binary system based on biotinylated MAb to Е2 domain of Сх43 and PEGylated liposomes with streptavidin (SAv) for C6 glioma cell culture in vivo.
