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CCC's dissertation 2014 4th version.pdf (5.4 MB)

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Inhibition of Epithelial-to-Mesenchymal Transition by Anti-tumor Agents in Cancer Cells

Chou, Chih-Chien
http://rave.ohiolink.edu/etdc/view?acc_num=osu1396875461

Abstract Details

2014, Doctor of Philosophy, Ohio State University, Pharmacy.
Epithelial-mesenchymal transition (EMT) is a critical process that confers to cancer cells the ability to invade basement membranes and metastasize to distant sites. Here, we report a novel function of the metabolic sensor adenosine monophosphate-activated protein kinase (AMPK) in suppressing EMT by modulating the Akt-MDM2-Foxo3 signaling axis. This mechanistic link was supported by the effects of siRNA-mediated knockdown and pharmacological activation of AMPK on epithelial (E-cadherin) and mesenchymal markers (vimentin, YB-1, Snail) in a panel of breast and prostate cancer cell lines. Exposure of cells to OSU-53, a novel allosteric AMPK activator, as well as metformin and AICAR, reversed their mesenchymal phenotype, which could be abrogated by AMPK silencing. This phenotypic change was mediated through Foxo3a activation as knockdown and ectopic expression of Foxo3a mimicked the effects of AMPK silencing and OSU-53-induced activation on these EMT markers, respectively. Mechanistically, Foxo3a activation led to the transactivation of the E-cadherin gene and repression of genes encoding EMT-inducing transcription factors. Evidence indicates that OSU-53 activated Foxo3a through two Akt-dependent pathways: nuclear localization by blocking Akt- and IKKß-mediated phosphorylation, and protein stabilization by cytoplasmic sequestration of MDM2, an E3 ligase responsible for Foxo3a degradation. This mode of activation contrasts with a previously reported in which AMPK increased Foxo3a transcriptional activity through direct phosphorylation without affecting its subcellular localization. Functionally, the suppressive effect of OSU-53 on EMT was demonstrated by its ability to block the invasive phenotypes of MDA-MB-231 and PC-3 cells in vitro and lung metastasis in the 4T1 orthotopic mammary cancer model.
Ching-Shih Chen (Advisor)
James Fuchs (Committee Member)
Matthew Ringel (Committee Member)
Tatiana Oberyszyn (Committee Member)
125 p.
Pharmacy Sciences
AMPK, EMT, OSU-53, Foxo3a, MDM2, breast cancer, prostate cancer, metabolic stress

Recommended Citations

Citations

  • Chou, C.-C. (2014). Inhibition of Epithelial-to-Mesenchymal Transition by Anti-tumor Agents in Cancer Cells [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1396875461

    APA Style (7th edition)

  • Chou, Chih-Chien. Inhibition of Epithelial-to-Mesenchymal Transition by Anti-tumor Agents in Cancer Cells. 2014. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1396875461.

    MLA Style (8th edition)

  • Chou, Chih-Chien. "Inhibition of Epithelial-to-Mesenchymal Transition by Anti-tumor Agents in Cancer Cells." Doctoral dissertation, Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1396875461

    Chicago Manual of Style (17th edition)

osu1396875461
251
© 2014, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.