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  • So studies are currently in

    2021-09-15

    So, studies are currently in progress to design drugs which could inhibit the main crosstalk components between interacting key pathways (Fig. 1).
    Wnt The Wnt family consists of 19 highly conserved glycoproteins serving as ligands which bind to the G-protein coupled 7-pass transmembrane receptor Frizzled (Fz) [25]. The Wnt proteins play a major role in the body, both during embryogenesis, directing the development of various organs and organ systems including the central nervous system, cardiovascular system, excretory (renal) system, and respiratory system [26], as well as during adulthood, by regulating self-renewal of tissues like hair follicles, growth plates of bones and intestinal crypt Vicriviroc maleate [27,28]. The Wnt signal transduction is broadly categorized into two pathways - canonical and non-canonical. The transduction of Wnt signal via the canonical pathway ultimately results in cytosolic stabilization of β-catenin (Fig. 2) and subsequently its translocation into the nucleus, followed by transcription of β-catenin responsive genes, while the non-canonical pathway is independent of β-catenin but is Ca2+ responsive, and results in Rho-associated protein kinase (ROCK) and c-Jun N-terminal Kinase (JNK)-mediated cytoskeletal responses besides transcriptional activation of targeted genes. β-catenin, once translocated to the nucleus via the canonical pathway, interacts with members of another set of transcription factors, namely T-cell factor/Lymphocyte enhancer factor (TCF/LEF), to activate the transcription of target genes [29].The Wnt proteins are secreted out of the cell through specialized transmembrane protein Wntless [30], but before its secretion, the Wnt proteins undergo addition of palmitate and glycan residues in order to effect proper internalization of the LRP (Lipoprotein-receptor related protein) 5/6 receptors which are the other group of receptors mediating the canonical Wnt signaling [31,32]. There is a cysteine-rich portion in the Frizzled receptor that is a conserved region [33], where multiple Wnt homologues bind; the binding propensity of these homologues have been attributed to be the determining factor for specificity in the cellular response among the homologues [34]. Deregulation in Wnt signaling has been reported in an array of malignancies ranging from hepatocellular carcinoma to acute and chronic myeloid leukemia, which includes hepatoblastoma, colorectal cancer, multiple myeloma, gastric cancer and Wilms’ tumor [17,[35], [36], [37], [38], [39]]. Moreover, aberrant Wnt signaling has largely been associated with the CSCs, where it has specifically been shown in case of CSCs from cutaneous origin requiring β-catenin to maintain their tumorigenic characteristics [40]. In the absence of a Wnt ligand, β-catenin is destabilized and degraded by the Adenomatous Polyposis Coli/ Axin/ Glycogen Synthase Kinase 3/ Protein Phosphatase 2 A (APC/Axin/GSK3/PP2A) complex, but these cells require the constitutive activity of β-catenin as a transcription factor, continuously translocating into nucleus and effecting cell proliferating genes transcription without any check. Dysregulation of Wnt pathway has also been documented in leukemic stem cells in Acute Myeloid Leukemia (AML) as compared to normal hematopoietic stem cells [41], with marked upregulation in the cascade proteins Adenomatous Polyposis Coli (APC) and Axin, a phenomenon to which leukemogenesis is attributed [42]. Wnt ligands could be secreted by a variety of Vicriviroc maleate mechanisms, like through exosome formation [43], on lipid protein particles [44], or direct solubilisation [45] through the plasma membrane, the various routes possibly determining their corresponding functions during development or maintenance. Though it is unclear what mechanism is prevalent in cancer development, however in breast cancer microenvironment, exosome-based signaling has been found [46].
    Hedgehog Like the Wnt family, the Hedgehog family of genes had also been first described in Drosophila, and are likewise tissue-patterning genes functioning during embryonic development but also highly active in adult tissue repair. There are three Hedgehog ligands which have been discovered so far – the Sonic Hedgehog (SHH), the Indian Hedgehog (IHH) and the Desert Hedgehog (DHH), SHH being the most widely-studied. All the Hedgehog ligands are secreted through various mechanisms, mostly via exosomes, and bind to the 12-pass transmembrane protein receptor Patched (PTCH). PTCH constitutively inhibits the activity of Smoothened (SMO), a 7-pass transmembrane protein also located in the cell membrane similar to the Fz receptors mediating the Wnt cascade, when no Hedgehog ligand is bound (Fig. 3). Upon a Hedgehog ligand binding event, the inhibitory effect of PTCH on SMO is removed and SMO then mediates the Hedgehog signal intracellularly. The signal is tranduced via the subsequent sequestration of the proteins Supressor of Fused (SUFU) and Costal (COS), thus releasing GLI proteins (GLI1/2, GLI3 is a transcriptional repressor) which ultimately translocate into the nucleus, thus activating transcription of Hedgehog target genes, which mainly result in cell proliferation, growth and survival. Also, similar to the Wnt signaling, the Hedgehog pathway also demonstrates two main types – canonical and non-canonical. While the canonical pathway follows the discussed PTCH1-SMO-GLI axis, the non-canonical pathway is SMO-independent [67]. Any pathway that allows the translocation of GLI1/2 to the nucleus to allow its activity as a transcriptional factor, are categorized under non-canonical pathways. These could be mediated by the integral cell signaling pathways like KRAS–MAPK/ERK, TGF-β, IGF, PI3K–AKT, TNF-α induced mTOR/S6K1 activation, and also inactivation of hSNF5 (also known as SMARCB1, known to be a regulator of chromatin remodelling).