title: Inhibition of p70S6K1 Activation by Pdcd4 Overcomes the Resistance to an IGF-1R/IR Inhibitor in Colon Carcinoma Cells.
abstract: Agents targeting insulin-like growth factor 1 receptor (IGF-1R) are being actively examined in clinical trials. Although there has been some initial success of single-agent targeting IGF-1R, attempts in later studies failed because of resistance. This study aimed to understand the effects of programmed cell death 4 (Pdcd4) on the chemosensitivity of the IGF-1R inhibitor OSI-906 in colorectal cancer cells and the mechanism underlying this impact. Using OSI-906-resistant and -sensitive colorectal cancer cells, we found that the Pdcd4 level directly correlates with cell chemosensitivity to OSI-906. In addition, tumors derived from Pdcd4 knockdown cells resist the growth inhibitory effect of OSI-906 in a colorectal cancer xenograft mouse model. Moreover, Pdcd4 enhances the antiproliferative effect of OSI-906 in resistant cells through suppression of p70S6K1 activation. Knockdown of p70S6K1, but not p70S6K2, significantly increases the chemosensitivity of OSI-906 in cultured colorectal cancer cells. Furthermore, the combination of OSI-906 and PF-4708671, a p70S6K1 inhibitor, efficiently suppresses the growth of OSI-906-resistant colon tumor cells in vitro and in vivo. Taken together, activation of p70S6K1 that is inhibited by Pdcd4 is essential for resistance to the IGF-1R inhibitor in colon tumor cells, and the combinational treatment of OSI-906 and PF-4708671 results in enhanced antiproliferation effects in colorectal cancer cells in vitro and in vivo, providing a novel venue to overcome the resistance to the IGF-1R inhibitor in treating colorectal cancer.
authors.affiliation: Department of Cancer Biology and Toxicology, College of Medicine, University of Kentucky, Lexington, Kentucky.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Cancer Biology and Toxicology, College of Medicine, University of Kentucky, Lexington, Kentucky.
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, Kentucky. Markey Cancer Center, College of medicine, University of Kentucky, Lexington, Kentucky.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Cancer Biology and Toxicology, College of Medicine, University of Kentucky, Lexington, Kentucky. Markey Cancer Center, College of medicine, University of Kentucky, Lexington, Kentucky. hyang3@uky.edu.
authors.forename: Hsin-Sheng
authors.initials: HS
authors.lastname: Yang
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D018938:Caco-2 Cells; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; D051017:Apoptosis Regulatory Proteins; D007093:Imidazoles; C114487:PDCD4 protein, human; C552719:PF-4708671; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D016601:RNA-Binding Proteins; D017526:Receptor, IGF Type 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa