title: Tristetraprolin mediates the anti-proliferative effects of metformin in breast cancer cells.
abstract: Metformin, which is a drug commonly prescribed to treat type 2 diabetes, has anti-proliferative effects in cancer cells; however, the molecular mechanisms underlying this effect remain largely unknown. The aim is to investigate the role of tristetraprolin (TTP), an AU-rich element-binding protein, in anti-proliferative effects of metformin in cancer cells. p53 wild-type and p53 mutant breast cancer cells were treated with metformin, and expression of TTP and c-Myc was analyzed by semi-quantitative RT-PCR, Western blots, and promoter activity assay. Breast cancer cells were transfected with siRNA against TTP to inhibit TTP expression or c-Myc and, after metformin treatment, analyzed for cell proliferation by MTS assay. Metformin induces the expression of tristetraprolin (TTP) in breast cancer cells in a p53-independent manner. Importantly, inhibition of TTP abrogated the anti-proliferation effect of metformin. We observed that metformin decreased c-Myc levels, and ectopic expression of c-Myc blocked the effect of metformin on TTP expression and cell proliferation. Our data indicate that metformin induces TTP expression by reducing the expression of c-Myc, suggesting a new model whereby TTP acts as a mediator of metformin's anti-proliferative activity in cancer cells.
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan, 680-749, Korea.
authors.forename: Indira
authors.initials: I
authors.lastname: Pandiri
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan, 680-749, Korea.
authors.forename: Yingqing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan, 680-749, Korea.
authors.forename: Yeonsoo
authors.initials: Y
authors.lastname: Joe
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan, 680-749, Korea.
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan, 680-749, Korea.
authors.forename: Jeongmin
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan, 680-749, Korea. chung@ulsan.ac.kr.
authors.forename: Hun Taeg
authors.initials: HT
authors.lastname: Chung
authors.affiliation: Department of Biological Sciences, University of Ulsan, Ulsan, 680-749, Korea. jwpark@ulsan.ac.kr.
authors.forename: Jeong Woo
authors.initials: JW
authors.lastname: Park
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D054697:Cytostatic Agents / Q000494:pharmacology*; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D008687:Metformin / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D051816:Tristetraprolin / Q000235:genetics* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D054697:Cytostatic Agents; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; C495901:TP53 protein, human; D051816:Tristetraprolin; D016159:Tumor Suppressor Protein p53; C497552:ZFP36 protein, human; D008687:Metformin
keywords: Anti-proliferation; Metformin; Tristetraprolin; c-Myc; p53