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

Abstract

BackgroundCancer 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 FindingsHuman 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/SignificanceThese 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.

Resveratrol inhibits the hedgehog signaling pathway and epithelial-mesenchymal transition and suppresses gastric cancer invasion and metastasis

“…This indicates that the EMT process is regulated by the Hh signaling pathway. Another previous study demonstrated that resveratrol could inhibit EMT in order to slow migration and invasion in pancreatic cancer cells (51).…”

Resveratrol, an activator of SIRT1, restores erectile function in streptozotocin-induced diabetic rats

“…6 It has also shown chemopreventative properties in certain forms of cancer and cardiovascular disorders and to increase longevity. [7][8][9] Moreover, resveratrol appears to protect against diabetes 10 by inducing silent information regulator 2-related enzymes 1 (sirtuin1, SIRT1). 11 In this study, we investigated the hypothesis that resveratrol improved erectile function in diabetes-induced ED by suppressing apoptosis and preventing oxidative stress in the corpus cavernosal and by upregulating SIRT1 in a streptozotocin (STZ)-induced diabetic rat model.…”

Gastric tumor-initiating CD44+ cells and epithelial-mesenchymal transition are inhibited by γ-secretase inhibitor DAPT

“…It has been proposed that transformed epithelial cells may activate embryonic programs for epithelial plasticity and switch from sessile and epithelial phenotypes to motile and mesenchymal phenotypes (30). Therefore, the induction of EMT may lead to the invasion of surrounding stroma, intravasation, dissemination and colonization of distant sites (31). Under the CSC hypothesis, sustained metastatic growth requires the dissemination of a CSC from the primary tumor followed by its reestablishment at a secondary site (32).…”