title: Adamantyl Retinoid-Related Molecules Induce Apoptosis in Pancreatic Cancer Cells by Inhibiting IGF-1R and Wnt/β-Catenin Pathways.
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.
authors.affiliation: John D Dingell VA MC, Wayne State University, Detroit, MI 48201, USA.
authors.forename: Lulu
authors.initials: L
authors.lastname: Farhana
authors.forename: Marcia I
authors.initials: MI
authors.lastname: Dawson
authors.forename: Jayanta K
authors.initials: JK
authors.lastname: Das
authors.forename: Farhan
authors.initials: F
authors.lastname: Murshed
authors.forename: Zebin
authors.initials: Z
authors.lastname: Xia
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Hadden
authors.forename: James
authors.initials: J
authors.lastname: Hatfield
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Fontana