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    • Various inhibitors have been developed

    2021-10-18

    Various inhibitors have been developed to target molecules present in these pathways. They include both man-made monoclonal sodium channel as well as small molecule membrane permeable inhibitors that often target kinases or phosphatases [5], [338], [348], [364]. In summary, these pathways are frequently dysregulated in human cancer and their abnormal function often leads to increased proliferation and contributes to tumorigenicity.
    Overview of the hedgehog (Hh) signaling pathway GSK-3 also can regulate the Hh signaling pathway. Suppression of GSK-3 activity decreases the Hh pathway. The Hh pathway has essential roles in development and segmental pattern formation and is also involved in neoplasia and other developmental diseases. Hh ligands include: desert hedgehog (DHH), Indian hedgehog (IHH) and sonic hedgehog (SHH). The Hh ligands interact with the 12-pass transmembrane receptor patched (PTCH1) to regulate developmental signaling [385]. Depending on the circumstances, Hhs can act as mitogens, or in other conditions, they may promote differentiation. Fig. 14 presents a brief overview of the Hh pathway and indicates where some of the key mutations in this pathway occur and have effects on certain cancers and developmental disorders. When a Hh binds PTCH1, PTCH1 is internalized and degraded. This results in the release of Smoothened (SMO), a G protein coupled receptor (GPCR). SMO then stimulates the dissociation of a suppressor of fused (SUFU)-glioma-associated oncogene homologue (GLI) complex. Upon stimulation of active SMO and dissociation of the SUFU/GLI complex, the transcription factors GLI1 and GLI2 can translocate to the nucleus and stimulate the transcription of certain genes including: BCL2, CCND1, GLI1, GLI2, IGF2, MYC, and PTCH1[386]. Thus there is yet another regulatory loop between GSK-3 and the Hh pathway. SUFU normally serves to inhibit the activity of GLI-1 by preventing the nuclear translocation of GLI-1. GSK-3 elevates Hh activity by phosphorylating SUFU that causes disassociation of SUFU from GLI3.
    The Notch signaling pathway and interactions with GSK-3 The Notch signaling pathway is another critical pathway regulated by GSK-3 [436], [437], [438]. Briefly, Notch signaling is critical in many cellular processes including cancer and is a therapeutic target [439], [440], [441], [442], [443], [444], [445]. Activation of the Notch pathway occurs after cell-to-cell interactions. A gamma secretase induces the activity of Notch protein stimulating the cleavage of Notch into the Notch intracellular domain (NICD). NICD can then translocate into the nucleus to regulate gene expression through its interactions with other transcription factors, HATs and other chromosomal proteins [441], [442], [443], [444], [445]. GSK-3 and Akt can have opposite effects on the Notch pathway [446], [447]. The transcriptional activity of NICD is increased upon GSK-3 phosphorylation. This phosphorylation event also increases the stability of NICD by preventing its proteasomal degradation [446]. GSK-3 phosphorylates NICD on the domain involved in nuclear localization. This increases the transcriptional activity of Notch [448]. On the other hand, the transcriptional activity of NICD is regulated negatively by Akt phosphorylation [447]. Some other studies have shown that phosphorylation of Notch1 by GSK-3 resulted in decreased levels of Notch1 as well as transcriptional activity [449], [450], [451]. Beta-catenin can also influence the transcriptional activity of Notch1/NICD [450]. Notch1 mutations are detected in approximately 50% of T-ALL patient samples. These T-ALL patients can be treated with γ-secretase inhibitors (GSIs). Mutant Notch1 will activate various signaling and apoptotic pathways, including: PI3K/PTEN/Akt/mTORC1/GSK-3 and c-Myc [452]. Additional targets of the miR-200 family include the Notch signaling pathway. The Notch pathway is also involved in EMT and metastasis. miR-200 can suppress Jagged 1, mastermind-like protein 2 (Maml2) and Maml3 which have effects on ZEB1/2 expression, that can in turn regulate miR-200 levels. Notch signaling (Jagged2) can regulate GATAs which will suppress miR-200. These pathways have multiple autoregulatory loops [209]. miR-200 prevented the metastasis of human prostate cancer cells by suppressing the Notch ligand Jagged2, Maml2 and Maml3 [453], [454]. Thus the PI3K/PTEN/Akt/mTORC1, Wnt/beta-catenin, GSK-3 pathways and miRs can interact and regulate Notch signaling.