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

• Published in: Experimental cell research 2016-05, Vol.344 (1), p.95-102
• Main Authors: Peek, Gregory W., Tollefsbol, Trygve O.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; AVOIDANCE; Axin Protein - genetics; Axin Protein - metabolism; CELL CYCLE; Cell Proliferation - drug effects; CHROMOSOMES; Cyclin D1; Cyclin D1 - genetics; Cyclin D1 - metabolism; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Down-Regulation - drug effects; ESTROGENS; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; GENES; Gonanes - pharmacology; GROWTH FACTORS; HEPARIN; hTERT; Humans; Immunoblotting; LIGANDS; MAMMARY GLANDS; MCF-7 Cells; NEOPLASMS; PERTURBATION THEORY; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation - drug effects; PLANT GROWTH; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-mdm2 - metabolism; PX-866; Raloxifene; Raloxifene Hydrochloride - pharmacology; Real-Time Polymerase Chain Reaction; RECEPTORS; REGULATIONS; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - drug effects; Smad Proteins - metabolism; Telomerase - genetics; Telomerase - metabolism; TRANSCRIPTION; TRANSCRIPTION FACTORS; Transcription signature; Transcription, Genetic - drug effects; Transforming Growth Factor beta - metabolism
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2016.03.022

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. •PX-866 and raloxifene affect the PI3K/Akt and TGF-β pathways.•PX-866 and raloxifene down-regulate genes up-regulated in cancer.•PX-866 and raloxifene decrease transcription of hTERT and Cyclin D1.•Pathological transcription signatures can identify new defense mechanisms.