Elevation of adenylate energy charge by angiopoietin-like 4 enhances epithelial–mesenchymal transition by inducing 14-3-3γ expression
| Autor: | Zhen Wei Tan, Jeremy Soon Kiat Chan, Ziqiang Teo, Justin Yin Hao Lee, Pengcheng Zhu, Terri Phua, Nguan Soon Tan, Luchun Li, Ming Keat Sng, Maegan Miang Kee Lim, Yinliang Li |
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| Přispěvatelé: | Lee Kong Chian School of Medicine (LKCMedicine), School of Biological Sciences |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
STAT3 Transcription Factor
0301 basic medicine Cancer Research Epithelial-Mesenchymal Transition Immunoblotting Transplantation Heterologous Adenylate kinase Mice SCID Biology 03 medical and health sciences Adenosine Triphosphate Mice Inbred NOD Cell Line Tumor Neoplasms Genetics Angiopoietin-Like Protein 4 Animals Humans Epithelial–mesenchymal transition Protein kinase A Molecular Biology Protein kinase B Cancer Mice Knockout Microscopy Confocal Kinase Signal transducing adaptor protein Hep G2 Cells Cell Biology Cell biology HEK293 Cells 030104 developmental biology 14-3-3 Proteins Biochemistry MCF-7 Cells Phosphorylation Original Article RNA Interference Mitogen-Activated Protein Kinases Signal transduction Signal Transduction |
| Zdroj: | Oncogene |
| Popis: | Metastatic cancer cells acquire energy-intensive processes including increased invasiveness and chemoresistance. However, how the energy demand is met and the molecular drivers that coordinate an increase in cellular metabolic activity to drive epithelial–mesenchymal transition (EMT), the first step of metastasis, remain unclear. Using different in vitro and in vivo EMT models with clinical patient’s samples, we showed that EMT is an energy-demanding process fueled by glucose metabolism-derived adenosine triphosphate (ATP). We identified angiopoietin-like 4 (ANGPTL4) as a key player that coordinates an increase in cellular energy flux crucial for EMT via an ANGPTL4/14-3-3γ signaling axis. This augmented cellular metabolic activity enhanced metastasis. ANGPTL4 knockdown suppresses an adenylate energy charge elevation, delaying EMT. Using an in vivo dual-inducible EMT model, we found that ANGPTL4 deficiency reduces cancer metastasis to the lung and liver. Unbiased kinase inhibitor screens and Ingenuity Pathway Analysis revealed that ANGPTL4 regulates the expression of 14-3-3γ adaptor protein via the phosphatidylinositol-3-kinase/AKT and mitogen-activated protein kinase signaling pathways that culminate to activation of transcription factors, CREB, cFOS and STAT3. Using a different mode of action, as compared with protein kinases, the ANGPTL4/14-3-3γ signaling axis consolidated cellular bioenergetics and stabilized critical EMT proteins to coordinate energy demand and enhanced EMT competency and metastasis, through interaction with specific phosphorylation signals on target proteins. MOE (Min. of Education, S’pore) Published version |
| Databáze: | OpenAIRE |
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