Functional modification of adipocytes by grape seed extract impairs their pro-tumorigenic signaling on colon cancer stem cells and the daughter cancer cells
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Sushil Kumar1,*, Dileep Kumar1,*, Komal Raina1,2, Rajesh Agarwal1,2, Chapla Agarwal1,2
1Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
2University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
*Contributed equally and share first authorship
Chapla Agarwal, e-mail: Chapla.Agarwal@UCDenver.edu
Keywords: colorectal cancer, obesity, chemoprevention, phytochemicals, adipocytes
Received: August 01, 2014 Accepted: September 07, 2014 Published: October 10, 2014
With global rise in obesity, it is imperative that we identify obesity-driven factors that increase growth and progression of colorectal cancer (CRC), and also discover and develop agents with anti-CRC efficacy under obese conditions. Here in, we investigated grape seed extract (GSE), a well-defined agent with both preventive and anti-CRC efficacy, for its potential to impair pro-tumorigenic signaling of adipocytes on CRC/colon cancer stem cells (CSCs) and associated molecular mechanisms, to control CRC under obese conditions. GSE treatment significantly decreased the growth and invasion promoting effects of both mouse and human adipocytes on CRC cells. Moreover, GSE exerted a direct inhibitory effect, as well as it strongly reduced the growth promoting signals of adipocytes, on colon CSCs. These GSE effects were associated with a decrease in both mRNA and protein levels of various CSC-associated molecules. Notably, GSE effects on adipocytes were not due to changes in lipid content, but by inducing the ‘browning’ of adipocytes as evidenced by an increase in UCP-1 mRNA level and mitochondriogenesis. Together, these findings, for the first time, suggest the ability of GSE to induce ‘brown remodeling’ of white adipocytes, which causes functional modification of adipocytes thus impairing their pro-tumorigenic signals on colon CSCs/CRC cells.
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