title: Down-regulation of hTERT and Cyclin D1 transcription via PI3K/Akt and TGF-β pathways in MCF-7 Cancer cells with PX-866 and Raloxifene.
abstract: Human telomerase reverse transcriptase (hTERT) is the catalytic and limiting component of telomerase and also a transcription factor. It is critical to the integrity of the ends of linear chromosomes and to the regulation, extent and rate of cell cycle progression in multicellular eukaryotes. The level of hTERT expression is essential to a wide range of bodily functions and to avoidance of disease conditions, such as cancer, that are mediated in part by aberrant level and regulation of cell cycle proliferation. Value of a gene in regulation depends on its ability to both receive input from multiple sources and transmit signals to multiple effectors. The expression of hTERT and the progression of the cell cycle have been shown to be regulated by an extensive network of gene products and signaling pathways, including the PI3K/Akt and TGF-β pathways. The PI3K inhibitor PX-866 and the competitive estrogen receptor ligand raloxifene have been shown to modify progression of those pathways and, in combination, to decrease proliferation of estrogen receptor positive (ER+) MCF-7 breast cancer cells. We found that combinations of modulators of those pathways decreased not only hTERT transcription but also transcription of additional essential cell cycle regulators such as Cyclin D1. By evaluating known expression profile signatures for TGF-β pathway diversions, we confirmed additional genes such as heparin-binding epidermal growth factor-like growth factor (HB EGF) by which those pathways and their perturbations may also modify cell cycle progression.
authors.affiliation: Department of Biology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Peek
authors.affiliation: Department of Biology, University of Alabama at Birmingham, Birmingham, AL, USA; Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA; Comprehensive Center for Healthy Aging, University of Alabama at Birmingham, Birmingham, AL, USA; Comprehensive Diabetes Center, University of Alabama at Birmingham, Birmingham, AL, USA; Nutrition Obesity Research Center, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: trygve@uab.edu.
authors.forename: Trygve O
authors.initials: TO
authors.lastname: Tollefsbol
mesh_terms: D060466:Axin Protein / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006067:Gonanes / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D061986:MCF-7 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D051785:Smad Proteins / Q000378:metabolism; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C491761:AXIN2 protein, human; D060466:Axin Protein; C530104:CCND1 protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006067:Gonanes; C496788:PX-866; D012333:RNA, Messenger; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D019938:Cyclin D1; D020849:Raloxifene Hydrochloride; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C509186:TERT protein, human; D019098:Telomerase
keywords: Cyclin D1; PX-866; Raloxifene; Transcription signature; hTERT