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  • STAR Methods br Acknowledgments We thank C Hong R Huang

    2021-09-18

    STAR★Methods
    Acknowledgments We thank C. Hong, R. Huang, and Z. Yu at the HHMI Janelia cryo-EM facility for help with microscope operation and data collection. We thank A. Müller, W. Kan, and W. Weis for help with the SEC-MALS analysis and M. Elazar and J. Glenn for the use of equipment. P. Lovelace, S. Weber, and the Stanford Stem Cell Institute FACS Core provided support. We thank H. Chuang and P. Jackson for help with DNA constructs. Part of the molecular graphics and analyses was performed with UCSF Chimera and UCSF ChimeraX, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from NIHR01-GM129325 and P41-GM103311. This work is partially supported by NIH grants R01GM102498 (to P.A.B.); R01GM098672, S10OD020054, and S10OD021741 (to Y.C.); and R35GM122530 (to W.C.). Y.C. and P.A.B. were investigators of the Howard Hughes Medical Institute.
    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 KH CB19 (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 cell cycle 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 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).