title: AKT1 Inhibits Epithelial-to-Mesenchymal Transition in Breast Cancer through Phosphorylation-Dependent Twist1 Degradation.
abstract: Epithelial-to-mesenchymal transition (EMT) is an essential physiologic process that promotes cancer cell migration, invasion, and metastasis. Several lines of evidence from both cellular and genetic studies suggest that AKT1/PKBα, but not AKT2 or AKT3, serves as a negative regulator of EMT and breast cancer metastasis. However, the underlying mechanism by which AKT1 suppresses EMT remains poorly defined. Here, we demonstrate that phosphorylation of Twist1 by AKT1 is required for β-TrCP-mediated Twist1 ubiquitination and degradation. The clinically used AKT inhibitor MK-2206, which possesses higher specificity toward AKT1, stabilized Twist1 and enhanced EMT in breast cancer cells. However, we discovered that resveratrol, a naturally occurring compound, induced β-TrCP-mediated Twist1 degradation to attenuate MK-2206-induced EMT in breast cancer cells. Taken together, our findings demonstrate that resveratrol counteracts the unexpected metastatic potential induced by anti-AKT therapy and therefore suggest that the addition of resveratrol to an anti-AKT therapeutic regimen may provide extra support for limiting EMT.
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Li
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Weiya
authors.initials: W
authors.lastname: Xia
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Seung-Oe
authors.initials: SO
authors.lastname: Lim
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan. Department of Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hsu
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Longfei
authors.initials: L
authors.lastname: Huo
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan. Department of Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Long-Yuan
authors.initials: LY
authors.lastname: Li
authors.affiliation: Institute of Molecular Biology, National Chung Hsing University, Taichung, Taiwan.
authors.forename: Chien-Chen
authors.initials: CC
authors.lastname: Lai
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Shih-Shin
authors.initials: SS
authors.lastname: Chang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yi-Hsin
authors.initials: YH
authors.lastname: Hsu
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hui-Lung
authors.initials: HL
authors.lastname: Sun
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jongchan
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hirohito
authors.initials: H
authors.lastname: Yamaguchi
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Dung-Fang
authors.initials: DF
authors.lastname: Lee
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan. Department of Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Chao-Kai
authors.initials: CK
authors.lastname: Chou
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jung-Mao
authors.initials: JM
authors.lastname: Hsu
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yun-Ju
authors.initials: YJ
authors.lastname: Lai
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, Texas.
authors.forename: Adam M
authors.initials: AM
authors.lastname: LaBaff
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Ding
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, Texas.
authors.forename: How-Wen
authors.initials: HW
authors.lastname: Ko
authors.affiliation: Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Fuu-Jen
authors.initials: FJ
authors.lastname: Tsai
authors.affiliation: Department of Biotechnology, Asia University, Taichung, Taiwan. Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Chang-Hai
authors.initials: CH
authors.lastname: Tsai
authors.affiliation: Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Hortobagyi
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan. Department of Biotechnology, Asia University, Taichung, Taiwan. Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, Texas. mhung@mdanderson.org.
authors.forename: Mien-Chie
authors.initials: MC
authors.lastname: Hung
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology*; D059748:Proteolysis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013267:Stilbenes / Q000494:pharmacology; D051879:Twist-Related Protein 1 / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D013267:Stilbenes; D051879:Twist-Related Protein 1; D044844:beta-Transducin Repeat-Containing Proteins; D051057:Proto-Oncogene Proteins c-akt; D000077185:Resveratrol