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  • It has been reported that CD glioma stem cells


    It has been reported that CD133+ glioma stem Ezetimibe are resistant to temozolomide (TMZ) therapy [155]. Dose dependent TMZ treatment of CD133+ cells enhanced activities of the Notch and SHh pathways [156]. Moreover, 500 μmol/L TMZ induced a significant upregulation of Gli1, HES1 and HES5 transcripts. A considerably higher apoptotic rate was noted in CD133+ cells in response to parallel treatment with GSI-1 (Notch inhibitor), cyclopamine (SHh pathway inhibitor) and TMZ [156].
    Crosstalk with different molecules WW domain containing oxidoreductase gene (WOX1) is a tumor suppressor that is frequently downregulated in glioblastoma cells. There was a significantly enhanced response to radiation therapy in glioblastoma cells reconstituted with WOX1. Another interesting finding of this research was that use of signaling inhibitor sensitized WOX1 expressing glioblastoma cells to radiation therapy [157]. The Integrin Beta-4 (ITGB4)/ FAK signaling axis plays a contributory role in regulation of migration and invasion of ovarian cancer cells induced by SHh. There was a 3-fold increase in ITGB4 in SHh treated ovarian SKOV3 cancer cells [158]. GANT61, an inhibitor of Gli1 and Gli2 was noted to be effective against SKOV3 cancer cells. ITGB4 was markedly reduced in cells treated with GANT61. Phosphorylation of FAK (Focal adhesion kinase) at 397th tyrosine residue was notably enhanced in SKOV3 cells stimulated with SHh. However, despite stimulation with SHh, treatment of SKOV3 cells with an anti-ITGB4 blocking antibody dramatically reduced FAK (Tyr397) phosphorylation [158]. GANT61 (25 mg/kg, three times per week) significantly reduced tumor growth in mice subcutaneously implanted with SKOV3 cells [158].
    Crosstalk between Hedgehog inhibition and other signaling pathways The Hedgehog pathway is a highly evolutionarily conserved signaling pathway [159]. In mammals, this pathway controls embryonic development but can also be over-activated in a wide diversity of human cancers, with great importance in the self renewal capacity of cancer stem-like cells [160]. The downstream activation of Gli transcription factors leads to the transcription of gene products that promote cell proliferation, cell renewal and survival (Fig. 2) [161]. Given the important role of this pathway in some cancers, the inhibition of the Hedgehog pathway is a potential and promising target for anticancer therapy. While the Hedgehog pathway contributes to tumorigenesis, many other pathways are involved in the sustenance of the carcinogenesis related processes, suggesting that the combined inhibition of the Hedgehog pathway and connected signaling pathways would be a better and effective strategy against some types of cancer. Crosstalk between Hedgehog signaling and a wide range of other signaling pathways has been evidenced. One of the most investigated connections consists of functional association of the Hh signaling with epidermal growth factor receptor (EGFR), as this latter is involved in the activation of many other signaling pathways such as phosphoinositide 3-kinase (PI3K)/AKT/mTOR, mitogen-activated protein kinases (MAPKs), signal transducer and activator of transcription (STAT), SRC/FAK pathway or phospholipase C [162]. Through its downstream effects, EGFR signaling regulates a broad spectrum of biological processes such as cell proliferation and survival. Aberrant activation of EGFR signaling is directly linked with the development and growth of tumor cells [162,163]. A wide range of in vitro studies have shown that Hedgehog and EGFR pathways synergize in the stimulation of cell proliferation and invasion. Indeed, alteration of at least one of the two signaling pathways is found in about one-third of all cancers; moreover, deregulation of both in the same tumor is common [46]. For example, cooperation between both pathways has been evidenced in neural stem cells, in medulloblastoma cells, in HaCaT keratinocytes and in prostate cancer cells [[164], [165], [166], [167]]. Cooperation between EGFR signaling and Hedgehog has been highlighted via induction of the RAS/RAF/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling [168,169]. In an in vivo animal human model of non small-cell lung cancer (NSCLC) with acquired resistance to EGFR-inhibitors, Hedgehog signaling demonstrated a significant role in mediating the resistance to the inhibitors, via favoring of the epithelial to mesenchymal transition (EMT) [170]. This cooperation was also found in head and neck squamous cell cancer (HNSCC) where significant reduction in cell proliferation and colony formation was reported after dual targeting of EGFR and Hedgehog pathways [171].