Akt/PKB-Mediated Phosphorylation of Twist1 Promotes Tumor Metastasis via Mediating Cross-Talk between PI3K/Akt and TGF-β Signaling Axes

Cancer Discovery - Tập 2 Số 3 - Trang 248-259 - 2012
Gui-Rong Xue1,2, David F. Restuccia1,2, Qiang Lan1, Debby Hynx1,2, Stephan Dirnhofer1,2, Daniel Heß1,2, Curzio Rüegg1, Brian A. Hemmings1,2
1Authors' Affiliations: 1Friedrich Miescher Institute for Biomedical Research, Basel; 2Department of Medicine, University of Fribourg, Fribourg; 3National Center for Competence in Research (NCCR) Molecular Oncology, Swiss Institute of Experimental Cancer Research, Ecole Polytechnique Fédérale de Lausanne (ISREC-EPFL), Lausanne; and 4Institute of Pathology, University of Basel, Basel, Switzerland
2Department of Medicine, University of Fribourg, Fribourg

Tóm tắt

Abstract Metastatic breast tumor cells display an epithelial–mesenchymal transition (EMT) that increases cell motility, invasion, and dissemination. Although the transcription factor Twist1 has been shown to contribute to EMT and cancer metastasis, the signaling pathways regulating Twist1 activity are poorly understood. Here, we show that Twist1 is ubiquitously phosphorylated in 90% of 1,532 invasive human breast tumors. Akt/protein kinase B (PKB)–mediated Twist1 phosphorylation promotes EMT and breast cancer metastasis by modulating its transcriptional target TGF-β2, leading to enhanced TGF-β receptor signaling, which in turn maintains hyperactive phosphoinositide 3-kinase (PI3K)/Akt signaling. Preventing phosphorylation of Twist1, as well as depletion of TGF-β2, significantly impaired the metastatic potential of cancer cells in vivo, indicating a key role of phosphorylated Twist1 (phospho-Twist1) in mediating cross-talk between the PI3K/Akt and TGF-β/Smad signaling axes that supports metastatic tumor development. Our results describe a novel signaling event linking PI3K/Akt hyperactivation in tumor cells to direct regulation of Twist1 activation and tumor metastasis. Significance: We identified the first phospho-Twist1 transcriptional target TGF-β2, which mediates cross-talk between PI3K/Akt and TGF-β signaling and promotes tumor metastasis. Our results thus illustrate a direct role of PI3K/Akt signaling in metastatic cancer development and suggest that Twist1 phosphorylation could be a potential therapeutic target in clinical cancer treatment. Cancer Discovery; 2(3); 248–59. ©2012 AACR. This article is highlighted in the In This Issue feature, p. 193

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