Resveratrol inhibits pancreatic cancer stem cell characteristics in human and KrasG12D transgenic mice by inhibiting pluripotency maintaining factors and epithelial-mesenchymal transition
| Autor: | Jenna Passarini, Su-Ni Tang, Dara Nall, Sharmila Shankar, Daniel Meeker, Rakesh K. Srivastava, Jay Sharma |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Homeobox protein NANOG
Pluripotent Stem Cells Epithelial-Mesenchymal Transition endocrine system diseases Cancer Treatment lcsh:Medicine Apoptosis Mice Transgenic Resveratrol Antioxidants Proto-Oncogene Proteins p21(ras) chemistry.chemical_compound Mice Cancer stem cell Cell Movement Pancreatic cancer Basic Cancer Research Stilbenes medicine Animals Humans Epithelial–mesenchymal transition Induced pluripotent stem cell lcsh:Science Nutrition Multidisciplinary biology CD44 lcsh:R medicine.disease Pancreatic Neoplasms chemistry Oncology Immunology Cancer research biology.protein Neoplastic Stem Cells Medicine lcsh:Q Stem cell Cancer Prevention Research Article Transcription Factors |
| Zdroj: | PLoS ONE, Vol 6, Iss 1, p e16530 (2011) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Background Cancer stem cells (CSCs) can proliferate and self-renew extensively due to their ability to express anti-apoptotic and drug resistant proteins, thus sustaining tumor growth. Therefore, the strategy to eradicate CSCs might have significant clinical implications. The objectives of this study were to examine the molecular mechanisms by which resveratrol inhibits stem cell characteristics of pancreatic CSCs derived from human primary tumors and Kras(G12D) transgenic mice. Methodology/principal findings Human pancreatic CSCs (CD133(+)CD44(+)CD24(+)ESA(+)) are highly tumorigenic and form subcutaneous tumors in NOD/SCID mice. Human pancreatic CSCs expressing high levels of CD133, CD24, CD44, ESA, and aldehyde dehydrogenase also express significantly more Nanog, Oct-4, Notch1, MDR1 and ABCG2 than normal pancreatic tissues and primary pancreatic cancer cells. Similarly, CSCs from Kras(G12D) mice express significantly higher levels of Nanog and Oct-4 than pancreatic tissues from Pdx-Cre mice. Resveratrol inhibits the growth (size and weight) and development (PanIN lesions) of pancreatic cancer in Kras(G12D) mice. Resveratrol inhibits the self-renewal capacity of pancreatic CSCs derived from human primary tumors and Kras(G12D) mice. Resveratrol induces apoptosis by activating capase-3/7 and inhibiting the expression of Bcl-2 and XIAP in human CSCs. Resveratrol inhibits pluripotency maintaining factors (Nanog, Sox-2, c-Myc and Oct-4) and drug resistance gene ABCG2 in CSCs. Inhibition of Nanog by shRNA enhances the inhibitory effects of resveratrol on self-renewal capacity of CSCs. Finally, resveratrol inhibits CSC's migration and invasion and markers of epithelial-mesenchymal transition (Zeb-1, Slug and Snail). Conclusions/significance These data suggest that resveratrol inhibits pancreatic cancer stem cell characteristics in human and Kras(G12D) transgenic mice by inhibiting pluripotency maintaining factors and epithelial-mesenchymal transition. In conclusion, resveratrol can be used for the management of pancreatic cancer. |
| Databáze: | OpenAIRE |
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