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Cilia loss sensitizes cells to transformation by activating the mevalonate pathway.
- Source :
-
The Journal of experimental medicine [J Exp Med] 2018 Jan 02; Vol. 215 (1), pp. 177-195. Date of Electronic Publication: 2017 Dec 13. - Publication Year :
- 2018
-
Abstract
- Although cilia loss and cell transformation are frequently observed in the early stage of tumorigenesis, the roles of cilia in cell transformation are unknown. In this study, disrupted ciliogenesis was observed in cancer cells and pancreatic cancer tissues, which facilitated oncogene-induced transformation of normal pancreatic cells (HPDE6C7) and NIH3T3 cells through activating the mevalonate (MVA) pathway. Disruption of ciliogenesis up-regulated MVA enzymes through β catenin-T cell factor (TCF) signaling, which synchronized with sterol regulatory element binding transcription factor 2 (SREBP2), and the regulation of MVA by β-catenin-TCF signaling was recapitulated in a mouse model of pancreatic ductal adenocarcinoma (PDAC) and human PDAC samples. Moreover, disruption of ciliogenesis by depleting Tg737 dramatically promoted tumorigenesis in the PDAC mouse model, driven by Kras <superscript>G12D</superscript> , which was inhibited by statin, an inhibitor of the MVA pathway. Collectively, this study emphasizes the crucial roles of cilia in governing the early steps of the transformation by activating the MVA pathway, suggesting that statin has therapeutic potential for pancreatic cancer treatment.<br /> (© 2018 Deng et al.)
- Subjects :
- Animals
Carcinoma, Pancreatic Ductal etiology
Carcinoma, Pancreatic Ductal metabolism
Carcinoma, Pancreatic Ductal pathology
Cell Line, Tumor
Cell Transformation, Neoplastic genetics
Gene Expression Profiling
Humans
Male
Mice
NIH 3T3 Cells
Oncogenes
Pancreatic Neoplasms etiology
Pancreatic Neoplasms metabolism
Pancreatic Neoplasms pathology
Sterol Regulatory Element Binding Protein 2
TCF Transcription Factors metabolism
Pancreatic Neoplasms
Cell Transformation, Neoplastic metabolism
Cilia pathology
Metabolic Networks and Pathways
Mevalonic Acid metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1540-9538
- Volume :
- 215
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- The Journal of experimental medicine
- Publication Type :
- Academic Journal
- Accession number :
- 29237705
- Full Text :
- https://doi.org/10.1084/jem.20170399