title: Inhibition of sonic hedgehog pathway and pluripotency maintaining factors regulate human pancreatic cancer stem cell characteristics.
abstract: Activation of the sonic hedgehog (SHh) pathway is required for the growth of numerous tissues and organs and recent evidence indicates that this pathway is often recruited to stimulate growth of cancer stem cells (CSCs) and to orchestrate the reprogramming of cancer cells via epithelial mesenchymal transition (EMT). The objectives of this study were to examine the molecular mechanisms by which (-)-epigallocatechin-3-gallate (EGCG), an active compound in green tea, inhibits self-renewal capacity of pancreatic CSCs and synergizes with quercetin, a major polyphenol and flavonoid commonly detected in many fruits and vegetables. Our data demonstrated that EGCG inhibited the expression of pluripotency maintaining transcription factors (Nanog, c-Myc and Oct-4) and self-renewal capacity of pancreatic CSCs. Inhibition of Nanog by shRNA enhanced the inhibitory effects of EGCG on self-renewal capacity of CSCs. EGCG inhibited cell proliferation and induced apoptosis by inhibiting the expression of Bcl-2 and XIAP and activating caspase-3. Interestingly, EGCG also inhibited the components of SHh pathway (smoothened, patched, Gli1 and Gli2) and Gli transcriptional activity. Furthermore, EGCG inhibited EMT by inhibiting the expression of Snail, Slug and ZEB1, and TCF/LEF transcriptional activity, which correlated with significantly reduced CSC's migration and invasion, suggesting the blockade of signaling involved in early metastasis. Furthermore, combination of quercetin with EGCG had synergistic inhibitory effects on self-renewal capacity of CSCs through attenuation of TCF/LEF and Gli activities. Since aberrant SHh signaling occurs in pancreatic tumorigenesis, therapeutics that target SHh pathway may improve the outcomes of patients with pancreatic cancer by targeting CSCs.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, and Medicine, University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Su-Ni
authors.initials: SN
authors.lastname: Tang
authors.forename: Junsheng
authors.initials: J
authors.lastname: Fu
authors.forename: Dara
authors.initials: D
authors.lastname: Nall
authors.forename: Mariana
authors.initials: M
authors.lastname: Rodova
authors.forename: Sharmila
authors.initials: S
authors.lastname: Shankar
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Srivastava
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000096:biosynthesis; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D053823:Hedgehog Proteins / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000096:biosynthesis; D006801:Humans; D000071317:Nanog Homeobox Protein; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010936:Plant Extracts / Q000494:pharmacology; D039904:Pluripotent Stem Cells; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D011794:Quercetin / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D051820:TCF Transcription Factors / Q000037:antagonists & inhibitors; D013662:Tea; D014158:Transcription, Genetic / Q000187:drug effects; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis
chemical_list: D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; C489427:MYC protein, human; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D010936:Plant Extracts; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; C509239:SHH protein, human; D051820:TCF Transcription Factors; D013662:Tea; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D002392:Catechin; D011794:Quercetin; C045651:epigallocatechin gallate; D053148:Caspase 3