Resveratrol Inhibits Pancreatic Cancer Stem Cell Characteristics in Human and KrasG12D Transgenic Mice by Inhibiting Pluripotency Maintaining Factors and Epithelial-Mesenchymal TransitionReportar como inadecuado




Resveratrol Inhibits Pancreatic Cancer Stem Cell Characteristics in Human and KrasG12D Transgenic Mice by Inhibiting Pluripotency Maintaining Factors and Epithelial-Mesenchymal Transition - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

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 KrasG12D 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 KrasG12D 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 KrasG12D mice. Resveratrol inhibits the self-renewal capacity of pancreatic CSCs derived from human primary tumors and KrasG12D 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 KrasG12D transgenic mice by inhibiting pluripotency maintaining factors and epithelial-mesenchymal transition. In conclusion, resveratrol can be used for the management of pancreatic cancer.



Autor: Sharmila Shankar, Dara Nall, Su-Ni Tang, Daniel Meeker, Jenna Passarini, Jay Sharma, Rakesh K. Srivastava

Fuente: http://plos.srce.hr/



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