Interestingly, as reported in the literature, both mechanisms have been observed and can explain the specificity of cell growth control induced by Cxs

Interestingly, as reported in the literature, both mechanisms have been observed and can explain the specificity of cell growth control induced by Cxs. Open in a separate window Figure 2 Connexin-mediated negative control of cell proliferation. junction-related proteins, the pannexins. Despite this complexity, the possible involvements of connexins and pannexins in cancer progression and the elucidation of the mechanisms they control may lead to use them as new targets to control cancer progression. In this review, the involvements of connexins and pannexins in these different topics (cancer cell growth, invasion/metastasis process, possible cancer therapeutic targets) are discussed. Keywords: cancer, connexin, growth control, invasion, metastasis, pannexin, therapeutics 1. Introduction The majority of cancers in adults are solid tumours [1]. Whatever their tissue origin, those tumours are characterized by two fundamental properties, which are, first, an uncontrolled cell proliferation forming the tumour itself and then an acquired invasion capacity leading to the dissemination of cancer cells in the organism. Fifty years of investigation have shown involvement of gap junctions (GJs) or their molecular components, the connexins (Cxs), in these two fundamental characteristics of cancer progression [2,3,4]. More recently, it appeared that the involvement of Cxs could be complicated by the fact that they can act independently from the establishment of gap-junctional intercellular communication (GJIC). For instance, Cxs may be involved in these mechanisms through their interactome to modulate signalling pathways [5] or by acting as hemichannels (Hcs) mediating autocrine/paracrine communication [6]. This last activity may overlap with pannexins (Panxs) which are Cx-related TA 0910 acid-type proteins (Figure 1) [7]. Open in a separate window Figure 1 Connexin and pannexin molecules and channels formed by these molecules. As molecules, connexins (Cx) and pannexins (Panx) have similar topology with four transmembrane and intracellular (Intra.) NH2 and COOH domains. In the left panels, both kinds of molecules are shown in a spread way to distinguish their topology (1) and in a condensed way (2) to better represent as transmembrane subunits of channels (centre panels) and gap junctions (right panel). In humans, 21 subtypes of connexins have been characterized, which are differentially expressed in tissues [8]. They are named according to their expected FGF7 molecular weight (kDa) from the smallest connexin (Cx23: 23 kDa) to the largest one (Cx62: 62 kDa). The best-known member of the connexin family is the connexin43 (Cx43) which is the most common in the organism. Only 3 pannexin subtypes are known in human (PANX1, PANX2, PANX3) [9,10]. Except for Cx26, connexins can be phosphorylated mostly at their intracellular COOH tail (red spots) [11]. The level of phosphorylation potentially modifies channel gating, interaction with intracellular or other membrane proteins (connexin TA 0910 acid-type interactome) and thus their function and life cycle [11,12]. So far, pannexins do not appear to be regulated by phosphorylation as connexins are but they are more characterized as potentially N-glycosylated (green spots) molecules at their extracellular (Extra.) domain. Both connexins and pannexins can aggregate to form hexameric transmembrane channels permitting the passive passage of ions (e.g., Ca2+) and small (<1C1.5 kDa) hydrophilic molecules such as nutrients (e.g., glucose: Glu), amino acids (e.g., glutamate: Glut), nucleotides (e.g., ATP) and second messengers (e.g., cAMP and IP3). Theoretically, connexin-made channels (connexons also called hemichannels) and pannexin-made channels (pannexons) are permeable to TA 0910 acid-type the same type of ions and molecules even if pannexons permeability has been mostly studied for ATP, Ca2+ and glutamate (Glut). Moreover, connexons from one cell can dock with connexons of juxtaposed cells forming intercellular channels aggregated in gap junctions which permit the TA 0910 acid-type direct intercellular transfer from cytosol to cytosol (gap-junctional intercellular communication, GJIC) of same ions and TA 0910 acid-type molecules as isolated connexons. So far, no pannexon-made gap junctions have been described in physiological/pathological conditions. The term connexon is mostly used to define the transmembrane unit of gap junctions. When isolated in the plasma membrane, connexons are usually called hemichannels and can open with various stimuli such as, for example, hypoxia. For clarity in the figure, putative phosphorylation sites (red spots) and N-glycosylated sites (green spots) are not shown in channels and gap junctions. Possible involvements of Cxs and Panxs in cancer progression and the elucidation of the mechanisms they control lead to their use as new possible targets to control cancer progression [13,14]. Here, we will review the involvement of Cxs and Panxs in these different topics, which are cancer cell proliferation, invasion/metastasis process and as possible targets.

Posted in MMP