These very first observations suggested that the lack of GJIC could contribute to the lack of cell growth control which characterizes tumorigenesis [18]

These very first observations suggested that the lack of GJIC could contribute to the lack of cell growth control which characterizes tumorigenesis [18]. as hemichannels, which mediate autocrine/paracrine communication. This complex involvement of connexins in malignancy progression is even more complicated by the fact that their hemichannel function may overlap with additional space junction-related proteins, the pannexins. Despite this complexity, the possible involvements of connexins and pannexins in malignancy progression and the elucidation of the mechanisms they control may lead to use them as fresh targets to control cancer progression. With this review, the involvements of connexins and pannexins in these different topics (malignancy cell growth, invasion/metastasis process, possible cancer therapeutic focuses on) are discussed. strong class=”kwd-title” Keywords: malignancy, connexin, growth control, invasion, metastasis, pannexin, therapeutics 1. Intro The majority of cancers in adults are solid tumours [1]. Whatever their cells source, those tumours GSK-5498A are characterized by two fundamental properties, which are, 1st, GSK-5498A an uncontrolled cell proliferation forming the tumour itself and then an acquired invasion capacity leading to the dissemination of malignancy cells in the organism. Fifty years of investigation have shown involvement of space junctions (GJs) or their molecular parts, the connexins (Cxs), in these two fundamental characteristics of malignancy progression [2,3,4]. More recently, it appeared the involvement of Cxs could be complicated by the fact that they can take action independently from your 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 proteins (Number 1) [7]. Open in a separate windows Number 1 Connexin and pannexin molecules and channels created by these molecules. As molecules, connexins (Cx) and pannexins (Panx) have related topology with four transmembrane and intracellular (Intra.) NH2 and COOH domains. In the remaining panels, both kinds of molecules are shown inside 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 space junctions (ideal panel). In humans, 21 subtypes of connexins have been characterized, which are differentially indicated GSK-5498A in cells [8]. They are named according to their expected molecular excess 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 being (PANX1, PANX2, PANX3) [9,10]. Except for Cx26, connexins can be phosphorylated mostly at their intracellular COOH tail (reddish places) [11]. The level of phosphorylation potentially modifies channel gating, connection with intracellular or additional membrane proteins (connexin interactome) and thus their function and existence cycle [11,12]. So far, pannexins do not look like controlled by phosphorylation as connexins are but they are more characterized as potentially N-glycosylated (green places) molecules at their extracellular (Extra.) website. 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 the same type of ions and molecules actually if pannexons permeability has been mostly analyzed for ATP, Ca2+ and glutamate (Glut). Moreover, connexons from one cell can dock with connexons of juxtaposed cells forming intercellular channels aggregated in space junctions which permit the direct intercellular transfer from cytosol to cytosol (gap-junctional intercellular communication, GJIC) of same ions and molecules as isolated connexons. So far, no pannexon-made space junctions have been explained in physiological/pathological conditions. The term connexon is mostly used to define the transmembrane unit of space junctions. When isolated in the plasma membrane, connexons are usually called hemichannels and may open with numerous stimuli such as, for example, hypoxia. For clarity in the number, putative phosphorylation sites (reddish places) and N-glycosylated sites (green places) are not shown in channels and space junctions. Possible involvements of Cxs and Panxs in malignancy progression and the elucidation of the mechanisms they control lead to their use as fresh possible targets to control cancer Pten progression [13,14]. Here, we will review the involvement of Cxs and Panxs in these different topics, which are malignancy cell proliferation, invasion/metastasis process and as possible targets for malignancy control. 2. Connexins and Pannexins Involvement in Tumour Cell Growth 2.1. Connexins Involvement in Tumour Cell Growth Shortly after their characterization, GJs were thought to be involved in growth rules [15]. This assumption was the consequence of the possibility to GSK-5498A estimate GJ functions through electrical coupling or diffusion of small hydrophilic fluorescent tracers [16,17]. By using such approaches,.