A sesquiterpene lactone from Siegesbeckia glabrescens suppresses Hedgehog/Gli-mediated transcription in pancreatic cancer cells

Abstract

Abstract. 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.

Rab23 promotes the cisplatin resistance of ovarian cancer via the Shh-Gli-ABCG2 signaling pathway

“…The dysregulated activation of the Shh signaling pathway in cancer cells is associated with tumor occurrence, drug resistance and poor cancer prognosis (18). Gli1 activates the target genes downstream of the Shh pathway (19,20). It has been reported that Rab23 is associated with the Shh signaling pathway, but whether this correlation is positive or negative is still under debate.…”

Dauricine suppresses the growth of pancreatic cancer in�vivo by modulating the Hedgehog signaling pathway

“…Smo is a proto-oncogene and a key factor in the Hh signaling pathway (50), which activates the downstream transcription factor of the Gli family. The Gli family includes three molecules: Gli1, Gli2 and Gli3 (51). Gli1 is a potent transcriptional activator (10); Gli2 also acts as a transcriptional activator, whereas Gli3 mainly acts as a transcriptional repressor (52).…”

“…However, some studies have demonstrated that the inhibitory effects of other natural products on pancreatic cancer are mediated by the inhibition of the Hh signaling pathway. An active component from Siegesbeckia glabrescens , germacranolide sesquiterpene lactone, inhibited Gli-mediated transcriptional activity in human pancreatic cancer AsPC-1 and PANC-1 cells, and decreased cancer cell proliferation and the expression of Gli-targeted genes (51). Deguelin, a natural compound from the flavonoid family, has been reported to suppress growth, migration and invasion, and to promote apoptosis in two pancreatic cancer cell lines, PANC-1 and BxPC-3, through suppression of the Hh signaling pathway (58).…”

Protective Effects of Standardized Siegesbeckia glabrescens Extract and Its Active Compound Kirenol against UVB-Induced Photoaging through Inhibition of MAPK/NF-��B Pathways

“…It is well evidenced that oxidative stress induces NF-κB associated with MMP expression in the skin [9]. It was reported that S. glabrescens, which has been long used as an herbal medicine to treat inflammatory diseases, inhibited inducible nitric oxide synthase and cyclooxygenase-2 expression in lipopolysaccharide-activated RAW 264.7 macrophages [27]. Accordingly, it is conceivable that SGE prevents UVB through activation of the MAPK and NF-κB pathways.…”