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

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, beta 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 theWnt/beta-catenin pathway as indicated by decreased beta-catenin nuclear localization and inhibited Wnt/beta-catenin activation of transcription factor TCF/LEF. Knockdown of beta-catenin using sh-RNA also induced apoptosis and inhibited growth in pancreatic cancer cells. Thus, 3Cl-AHPC and AHP3 induce apoptosis in pancreatic cancer cells and cancer stem-like cells andmay serve as an important potential therapeutic agent in the treatment of pancreatic cancer.