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Journal of Oncology
Volume 2012, Article ID 796729, 14 pages
http://dx.doi.org/10.1155/2012/796729
Research Article

Adamantyl Retinoid-Related Molecules Induce Apoptosis in Pancreatic Cancer Cells by Inhibiting IGF-1R and Wnt/β-Catenin Pathways

1John D Dingell VA MC, Wayne State University, Detroit, MI 48201, USA
2Department of Oncology, Wayne State University, Detroit, MI 48201, USA
3Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
4Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA
5Department of Neurobiology, Harvard University, Cambridge, MA 02138, USA

Received 31 October 2011; Revised 17 January 2012; Accepted 30 January 2012

Academic Editor: Reidar Grenman

Copyright © 2012 Lulu Farhana et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Pancreatic carcinoma has a dismal prognosis as it often presents as locally advanced or metastatic. We have found that exposure to adamantyl-substituted retinoid-related (ARR) compounds 3-Cl-AHPC and AHP3 resulted in growth inhibition and apoptosis induction in PANC-1, Capan-2, and MiaPaCa-2 pancreatic cancer cell lines. In addition, AHP3 and 3-Cl-AHPC inhibited growth and induced apoptosis in spheres derived from the CD44+/CD24+ (CD133+/EpCAM+) stem-like cell population isolated from the pancreatic cancer cell lines. 3-Cl-AHPC-induced apoptosis was preceded by decreasing expression of IGF-1R, cyclin D1, β-catenin, and activated Notch-1 in the pancreatic cancer cell lines. Decreased IGF-1R expression inhibited PANC-1 proliferation, enhanced 3-Cl-AHPC-mediated apoptosis, and significantly decreased sphere formation. 3-Cl-AHPC inhibited the Wnt/β-catenin pathway as indicated by decreased β-catenin nuclear localization and inhibited Wnt/β-catenin activation of transcription factor TCF/LEF. Knockdown of β-catenin using sh-RNA also induced apoptosis and inhibited growth in pancreatic cancer cells. Thus, 3-Cl-AHPC and AHP3 induce apoptosis in pancreatic cancer cells and cancer stem-like cells and may serve as an important potential therapeutic agent in the treatment of pancreatic cancer.