Inhibition of sonic hedgehog pathway and pluripotency maintaining factors regulate human pancreatic cancer stem cell characteristics

• Published in: International journal of cancer Vol. 131; no. 1; pp. 30 - 40
• Main Authors: Tang, Su-Ni, Fu, Junsheng, Nall, Dara, Rodova, Mariana, Shankar, Sharmila, Srivastava, Rakesh K.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.07.2012; Wiley-Blackwell; Wiley Subscription Services, Inc
• Subjects: Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Cancer; cancer stem cells; Caspase; Caspase 3 - biosynthesis; Catechin - analogs & derivatives; Catechin - pharmacology; Cell activation; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Drug Synergism; EGCG; Epigallocatechin gallate; epithelial mesenchymal transition; Epithelial-Mesenchymal Transition - drug effects; Flavonoids; Gastroenterology. Liver. Pancreas. Abdomen; Green tea; Hedgehog protein; Hedgehog Proteins - metabolism; Homeodomain Proteins - biosynthesis; Humans; LEF/TCF protein; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical research; Medical sciences; Metastases; Molecular modelling; Myc protein; Nanog Homeobox Protein; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Octamer Transcription Factor-3 - biosynthesis; Pancreas; Pancreatic cancer; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Plant Extracts - pharmacology; Pluripotency; pluripotency maintaining factors; Pluripotent Stem Cells; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; Proto-Oncogene Proteins c-myc - biosynthesis; Quercetin; Quercetin - pharmacology; RNAi; Rodents; Signal transduction; Signal Transduction - drug effects; Snail protein; sonic hedgehog pathway; Stem cells; TCF Transcription Factors - antagonists & inhibitors; Tea; Transcription factors; Transcription, Genetic - drug effects; Tumorigenesis; Tumors; X-Linked Inhibitor of Apoptosis Protein - biosynthesis; XIAP protein; Human; RNAi; RNA interference; Stem cell; EGCG; sonic hedgehog pathway; Malignant tumor; pluripotency maintaining factors; Cell transformation; Gene silencing; pancreatic cancer; Cancerology; Hedgehog protein; Pancreas cancer; Digestive diseases; Inhibitor; Epithelial mesenchymal transition; cancer stem cells; Tumor cell; Pluripotency; Cancer; Pancreatic disease
• ISSN: 0020-7136; 1097-0215; 1097-0215
• DOI: 10.1002/ijc.26323

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.