title: Functional modification of adipocytes by grape seed extract impairs their pro-tumorigenic signaling on colon cancer stem cells and the daughter cancer cells.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colovado Anshutz Medical Campus, Aorova, CO, USA. Contributed equally and share first authorship.
authors.forename: Sushil
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colovado Anshutz Medical Campus, Aorova, CO, USA. Contributed equally and share first authorship.
authors.forename: Dileep
authors.initials: D
authors.lastname: Kumar
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colovado Anshutz Medical Campus, Aorova, CO, USA. University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Komal
authors.initials: K
authors.lastname: Raina
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colovado Anshutz Medical Campus, Aorova, CO, USA. University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Agarwal
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colovado Anshutz Medical Campus, Aorova, CO, USA. University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Chapla
authors.initials: C
authors.lastname: Agarwal
mesh_terms: D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D056604:Grape Seed Extract / Q000494:pharmacology*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D056604:Grape Seed Extract