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  • Introduction The Hedgehog Hh signaling

    2021-10-26

    Introduction The Hedgehog (Hh) signaling pathway regulates embryonic organogenesis, tissue patterning, and cell differentiation (Armas-Lopez et al., 2017, Ingham and McMahon, 2013). Aberrant activation of Hh signaling pathway contributes to tumor formation and development of various cancers including pancreatic cancer (Jiang and Hui, 2008, Pasca di Magliano and Hebrok, 2003). In the presence of Sonic hedgehog (Shh) ligand, the 12-pass transmembrane receptor (Patched, Ptch) can release repressed Smoothened (Smo). This induces nuclear translocation of Gli activator and activation of target gene expressions (Lum and Beachy, 2004, McMahon et al., 2003). In the absence of Hh ligands, Ptch restrains Smo, resulting in nuclear translocation of Gli repressor to switch off Hh target gene expression (Pan, Bai, Joyner, & Wang, 2006). There are three members of Gli transcription factors: Gli1, Gli2, and Gli3 (Hu et al., 2006). Gli1 and Gli2 can activate the expression of target genes related to cell growth and survival (Aberger and Ruiz, 2014, Hui et al., 1994, Persson et al., 2002). Gli2 may be an effective transcription factor in the absence of Gli1 (Bai & Joyner, 2001). However, Gli3 is a transcriptional repressor of Hh signaling (Hu et al., 2006). Direct target genes by Gli-mediated transcription are Hh pathway regulators such as Gli1, Gli2, Ptch (Agren et al., 2004, Hegde et al., 2008, Regl et al., 2002), and Endoxifen regulator such as FoxM1 (Teh et al., 2002). Recently, many studies have demonstrated that Hh signaling pathway is constitutively activated in pancreatic cancer. High level of Gli1 as the last stage in Hh signaling pathway is a significant indicator of tumor growth and aggressiveness in pancreatic cancer (Lauth and Toftgard, 2011, Liu et al., 2015, Onishi and Katano, 2014, Thayer et al., 2003). Therefore, interference of Gli might be a good therapeutic strategy to treat cancers accompanying highly activated Hh signaling pathway. Z-Ajoene, an organosulfur compound from garlic (Allium sativum), has antioxidant, antimicrobial, antithrombotic, and anti-inflammatory activities (Choi et al., 2018, Kay et al., 2010, Lee et al., 2012, Srivastava and Tyagi, 1993). Z-Ajoene has been reported to possess anti-proliferative and Endoxifen apoptotic effects on several cancer cells by activating endoplasmic reticulum stress, caspase-3, and ERK/p38 (Hassan, 2004, Jung et al., 2014, Kaschula et al., 2016, Kaschula et al., 2010). Herein, we report effects of Z-ajoene on Gli-mediated transcription at Hh pathway and proliferation of pancreatic cancer cells.
    Materials and methods
    Results
    Discussion Garlic has been consumed as a spice and a folk medicine since ancient times for cardio-protective and health benefits as well as for treatment of cancers (Adaki et al., 2014, Block et al., 1984, Khatua et al., 2013). Z-Ajoene, an organosulfur compound derived from allicin, has been isolated from garlic (Allium sativum). Biological activities of Z-ajoene include inhibition of platelet activation, enhancement of host defense against mycobacteria, and suppression of cancer cell proliferation (Choi et al., 2018, Jung et al., 2014, Teranishi et al., 2003). Several plant-derived molecules such as resveratrol, curcumin, zerumbone, and physalin B have been reported as modulators of Hh/Gli signaling pathway (Hosoya et al., 2008, Mohapatra et al., 2015). Our previous studies have demonstrated that a sesquiterpene lactone and diarylheptanoids from Siegesbeckia glabrescens, Alpinia officinarum and Alnus japonica can inhibit the Hh/Gli signaling pathway (Dong et al., 2017, Lee et al., 2016). Herein, we report that Z-ajoene (Fig. 1A) from garlic can also affect the Hh/Gli signaling pathway. While tightly regulated Hh pathway is responsible for coordinating cellular growth and embryo development, dysregulation of Hh pathway is involved in the formation, development, and aggressiveness of tumors, especially pancreatic cancer (Lauth and Toftgard, 2011, Xie et al., 2013). Hh pathway is activated with a series of signal cascade such as Shh ligand binding to Ptch, Smo activation and initiation of Gli-mediated transcription. Recent evidence suggests that constitutive activation of Gli is associated with tumor formation and growth (Kasper et al., 2006, Pietrobono et al., 2018). Although Smo antagonists have been reported as therapuetic candidates for various cancers (Fendrich et al., 2011, Ibuki et al., 2013), their therapeutic efficacies in preclinical and clinical cancer models are not promising (Rimkus et al., 2016). Recent studies have shown that acquired resistance to Smo inhibition is linked to mutations in Smo and aberrant activation of Gli or upregulation of synergic signals such as PI3K signaling (Benvenuto et al., 2016, Lauth and Toftgard, 2007). Resistance against Smo antagonist (vismodegib) has already been reported in patients with advanced or metastatic solid tumors (Atwood et al., 2012, Gonnissen et al., 2015, LoRusso et al., 2011). Another study has reported that GANT 61 (a Gli inhibitor) shows therapeutic effects on colon cancer cells that are resistance to Smo inhibitors (cyclopamine or GDC-0449) (Agyeman, Mazumdar, & Houghton, 2012). Therefore, the inhibition of Gli has been recognized as an efficient strategy to regulate the Hh signaling pathway for cancer therapy.