Gli-mediated transcriptional activity in human pancreatic cancer PANC-1 and AsPC-1 cells, which resulted in reduced cancer cell proliferation and downregulated expression of the Gli-target genes, Gli1 and cyclin D1. A sesquiterpene lactone

Pancreatic cancer is aggressive and therefore difficult to treat; however, continued efforts have been made with the aim of developing an effective therapy against the disease. The Hedgehog (Hh) signaling pathway is reportedly involved in the proliferation and survival of pancreatic cancer cells. The transcription factor glioma-associated oncogene (Gli) is a key component of the Hh signaling pathway and the primary effector of pancreatic cancer development. Inhibiting Gli is a proven therapeutic strategy for this disease. The present study examined the regulation of Gli and the expression of its target genes to identify an inhibitor of the Sonic Hh (Shh) pathway. A germacranolide sesquiterpene lactone (GSL) was isolated from Siegesbeckia glabrescens as an inhibitor of Gli-mediated transcription. The results demonstrated that GSL inhibited Shh-induced osteoblast differentiation and Gli homolog 1 (Gli1)-mediated transcriptional activity in mesenchymal C3H10T1/2 stem cells. Furthermore, GSL suppressed Gli-mediated transcriptional activity in human pancreatic cancer PANC-1 and AsPC-1 cells, which resulted in reduced cancer cell proliferation and downregulated expression of the Gli-target genes, Gli1 and cyclin D1. A sesquiterpene lactone from S. glabrescens may therefore serve as a candidate for the treatment of Hh/Gli-dependent pancreatic cancer. Introduction Pancreatic cancer is currently one of the leading causes of cancer-associated mortality in industrialized countries, with an incidence rate equaling its mortality rate (1). The number of newly diagnosed cases and mortalities per 100,000 individuals are 12.4 and 10.9, respectively, according to the National Cancer Institute (Bethesda, MD, USA; http://seer. cancer.gov). Despite research efforts, there has been limited progress regarding the treatment of this disease; therefore, novel strategies to identify new therapeutic agents are urgently required. The Hedgehog (Hh) signaling pathway is critical for morphogenesis signaling and is inappropriately activated in patients with pancreatic cancer (2,3). In addition, this pathway is associated with the growth and metastasis of various types of tumors, including pancreatic cancer (4,5). Therefore, the Hh pathway serves as a therapeutic target, and inhibitors of Hh signaling may function as novel therapeutic drugs for the treatment of pancreatic cancer. The Hedgehog (Hh) pathway regulates embryonic organogenesis and tissue growth (6), and is activated by Hh ligands, including Sonic Hh (Shh), which binds to a 12-pass transmembrane spanning receptor known as Patched (Ptch) (7). Binding of the Hh ligand to Ptch relieves repression of a 7-pass transmembrane receptor called Smoothened (Smo) (8). Released Smo activates the signaling pathway, resulting in release of the glioma-associated oncogene (Gli) transcription factor family [including Gli homolog 1 (Gli1), Gli2 and Gli3], which translocate to the nucleus and trigger expression of Gli target genes, such as Gli1 and cyclin D1, for cell growth (9). Inhibitors of Smo in the Hh pathway have been a frequent focus of therapeutic drug development and have been evaluated in preclinical models (10,11). However, resistance to Smo inhibitors may develop clinically (12,13). Smo inhibitors are ineffective in tumors accompanied by overactivated Gl, downstream of Smo (14). Thus, Gli, which is downstream of Smo, is an important target for repressing activated Hh signaling. Several studies have reported that Gli1 and Gli2 are the primary transcriptional effectors involved in tumor formation (15,16). In addition, the importance of Gli1 in tumor progression and development is well recognized in human cell culture systems. A number of studies have demonstrated that targeting Gli1 may be a promising cancer therapeutic strategy (17,18). A sesquiterpene lactone from Siegesbeckia glabrescens suppresses Hedgehog/Gli‐mediated transcription in pancreatic cancer cells HWA JIN LEE1, QIAN WU2, HUA LI2, GYU-UN BAE2, AN KEUN KIM2 and JAE-HA RYU2 1Department of Natural Medicine Resources, Semyung University, Jecheon, Chungcheongbuk-do 390-711; 2Research Center for Cell Fate Control and College of Pharmacy, Sookmyung Women's University, Seoul 140-742, Republic of Korea Received May 7, 2015; Accepted June 16, 2016 DOI: 10.3892/ol.2016.4994 Correspondence to: Professor Jae-Ha Ryu, Research Center for Cell Fate Control and College of Pharmacy, Sookmyung Women's University, 52 Hyochangwon-Gil, Yongsan-Gu, Seoul 140-742,