TY - JOUR
T1 - Peroxisome proliferator-activated receptor-γ inhibits transformed growth of non-small cell lung cancer cells through selective suppression of snail
AU - Choudhary, Rashmi
AU - Li, Howard
AU - Winn, Robert A.
AU - Sorenson, Amber L.
AU - Weiser-Evans, Mary C.M.
AU - Nemenoff, Raphael A.
N1 - Funding Information:
Address all correspondence to: Raphael A. Nemenoff, Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, C-281, 12700 E 19th Ave, Aurora, CO 80045. E-mail: Raphael.Nemenoff@ucdenver.edu 1This work was supported by grants from the National Institutes of Health (CA103618, CA108610, and CA58187) as well as a University of Colorado Cancer Center Seed Grant to Dr. Weiser-Evans. 2This article refers to supplementary materials, which are designated by Figures W1 and W2 and are available online at www.neoplasia.com. Received 22 September 2009; Revised 5 January 2010; Accepted 6 January 2010 Copyright © 2010 Neoplasia Press, Inc. All rights reserved 1522-8002/10/$25.00 DOI 10.1593/neo.91638
PY - 2010/3
Y1 - 2010/3
N2 - Work from our laboratory and others has demonstrated that activation of the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) inhibits transformed growth of non-small cell lung cancer (NSCLC) cell lines in vitro and in vivo. We have demonstrated that activation of PPARγ promotes epithelial differentiation of NSCLC by increasing expression of E-cadherin, as well as inhibiting expression of COX-2 and nuclear factor-κB. The Snail family of transcription factors, which includes Snail (Snail1), Slug (Snail2), and ZEB1, is an important regulator of epithelial-mesenchymal transition, aswell as cell survival. The goal of this studywas to determine whether the biological responses to rosiglitazone, a member of the thiazolidinedione family of PPARγ activators, are mediated through the regulation of Snail family members. Our results indicate that, in two independent NSCLC cell lines, rosiglitazone specifically decreased expression of Snail, with no significant effect on either Slug or ZEB1. Suppression of Snail using short hairpin RNA silencing mimicked the effects of PPARγ activation, in inhibiting anchorage-independent growth, promoting acinar formation in three-dimensional culture, and inhibiting invasiveness. This was associated with the increased expression of E-cadherin and decreased expression of COX-2 andmatrixmetaloproteinases. Conversely, overexpression of Snail blocked the biological responses to rosiglitazone, increasing anchorage-independent growth, invasiveness, and promoting epithelial-mesenchymal transition. The suppression of Snail expression by rosiglitazone seemed to be independent of GSK-3 signaling but was rather mediated through suppression of extracellular signal-regulated kinase activity. These findings suggest that selective regulation of Snail may be critical in mediating the antitumorigenic effects of PPARγ activators.
AB - Work from our laboratory and others has demonstrated that activation of the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) inhibits transformed growth of non-small cell lung cancer (NSCLC) cell lines in vitro and in vivo. We have demonstrated that activation of PPARγ promotes epithelial differentiation of NSCLC by increasing expression of E-cadherin, as well as inhibiting expression of COX-2 and nuclear factor-κB. The Snail family of transcription factors, which includes Snail (Snail1), Slug (Snail2), and ZEB1, is an important regulator of epithelial-mesenchymal transition, aswell as cell survival. The goal of this studywas to determine whether the biological responses to rosiglitazone, a member of the thiazolidinedione family of PPARγ activators, are mediated through the regulation of Snail family members. Our results indicate that, in two independent NSCLC cell lines, rosiglitazone specifically decreased expression of Snail, with no significant effect on either Slug or ZEB1. Suppression of Snail using short hairpin RNA silencing mimicked the effects of PPARγ activation, in inhibiting anchorage-independent growth, promoting acinar formation in three-dimensional culture, and inhibiting invasiveness. This was associated with the increased expression of E-cadherin and decreased expression of COX-2 andmatrixmetaloproteinases. Conversely, overexpression of Snail blocked the biological responses to rosiglitazone, increasing anchorage-independent growth, invasiveness, and promoting epithelial-mesenchymal transition. The suppression of Snail expression by rosiglitazone seemed to be independent of GSK-3 signaling but was rather mediated through suppression of extracellular signal-regulated kinase activity. These findings suggest that selective regulation of Snail may be critical in mediating the antitumorigenic effects of PPARγ activators.
UR - http://www.scopus.com/inward/record.url?scp=77949580004&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77949580004&partnerID=8YFLogxK
U2 - 10.1593/neo.91638
DO - 10.1593/neo.91638
M3 - Article
C2 - 20234816
AN - SCOPUS:77949580004
SN - 1522-8002
VL - 12
SP - 224
EP - 234
JO - Neoplasia
JF - Neoplasia
IS - 3
ER -