Rapalog resistance is associated with mesenchymal-type changes in Tsc2-null cells

Scientific Reports
Matthildi ValianouAristotelis Astrinidis

Abstract

Tuberous Sclerosis Complex (TSC) and Lymphangioleiomyomatosis (LAM) are caused by inactivating mutations in TSC1 or TSC2, leading to mTORC1 hyperactivation. The mTORC1 inhibitors rapamycin and analogs (rapalogs) are approved for treating of TSC and LAM. Due to their cytostatic and not cytocidal action, discontinuation of treatment leads to tumor regrowth and decline in pulmonary function. Therefore, life-long rapalog treatment is proposed for the control of TSC and LAM lesions, which increases the chances for the development of acquired drug resistance. Understanding the signaling perturbations leading to rapalog resistance is critical for the development of better therapeutic strategies. We developed the first Tsc2-null rapamycin-resistant cell line, ELT3-245, which is highly tumorigenic in mice, and refractory to rapamycin treatment. In vitro ELT3-245 cells exhibit enhanced anchorage-independent cell survival, resistance to anoikis, and loss of epithelial markers. A key alteration in ELT3-245 is increased β-catenin signaling. We propose that a subset of cells in TSC and LAM lesions have additional signaling aberrations, thus possess the potential to become resistant to rapalogs. Alternatively, when challenged with rapalogs TS...Continue Reading

References

Sep 3, 1996·Proceedings of the National Academy of Sciences of the United States of America·M FriedlanderD A Cheresh
Sep 4, 1998·Science·T C HeK W Kinzler
Feb 17, 1999·Proceedings of the National Academy of Sciences of the United States of America·B MannC Hanski
Dec 11, 1999·Nucleic Acids Research·M Kanehisa, S Goto
May 24, 2000·Proceedings of the National Academy of Sciences of the United States of America·T CarsilloE P Henske
Dec 26, 2001·Nucleic Acids Research·Ron EdgarAlex E Lash
Jan 4, 2003·The Journal of Biological Chemistry·Baldwin C MakRaymond S Yeung
Jun 19, 2003·Oncogene·Yuhong ChenDavid A Foster
Jan 24, 2004·Angiogenesis·Riccardo E NisatoMichael S Pepper
Jul 14, 2005·Gastroenterology·Xinping TanSatdarshan P S Monga
Feb 3, 2006·Annals of Neurology·David Neal FranzKerry R Crone
Aug 26, 2006·American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation·Ralf WieneckeMatthias Kretzler
Nov 3, 2006·American Journal of Respiratory Cell and Molecular Biology·George SuJean-François Pittet
Nov 24, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Lanie K FrancisIrene M Ghobrial
Jan 11, 2008·The New England Journal of Medicine·John J BisslerDavid N Franz
May 10, 2008·The Biochemical Journal·Jingxiang Huang, Brendan D Manning
Nov 6, 2008·Cell Stem Cell·Derk ten BergeRoel Nusse
Feb 10, 2009·Proceedings of the National Academy of Sciences of the United States of America·Jane J YuElizabeth P Henske
Apr 28, 2009·American Journal of Respiratory Cell and Molecular Biology·Po-Shun LeeDavid J Kwiatkowski
Sep 2, 2009·Molecular and Cellular Biology·Christian C DibbleBrendan D Manning
Nov 17, 2009·Proceedings of the National Academy of Sciences of the United States of America·Ichiro OtaStephen J Weiss
Dec 10, 2009·Molecular and Cellular Biology·Louis-Andre JulienPhilippe P Roux
Jul 1, 2010·Journal of Cellular Physiology·Ping LiuMichael J Wilson
Sep 4, 2010·The American Journal of Pathology·Elizabeth A BarnesRaymond S Yeung
Mar 18, 2011·The New England Journal of Medicine·Francis X McCormackUNKNOWN MILES Trial Group
Mar 29, 2011·Biochimica Et Biophysica Acta·Xinbo ZhangArun K Rishi
Jun 22, 2011·Annals of Internal Medicine·Diane SeibertThomas N Darling
Jul 19, 2011·Hematology/oncology Clinics of North America·Martin H VossRobert J Motzer
Nov 19, 2011·Journal of the American Society of Nephrology : JASN·Weichun HeYouhua Liu
Jul 17, 2012·Molecular Cell·Christian C DibbleBrendan D Manning
Sep 20, 2012·The Journal of Biological Chemistry·Michael W HanceJennifer S Isaacs
Mar 26, 2013·American Journal of Respiratory Cell and Molecular Biology·Chenggang LiJane J Yu
Sep 24, 2013·Pediatric Neurology·Hope NorthrupUNKNOWN International Tuberous Sclerosis Complex Consensus Group
May 28, 2014·Molecular Carcinogenesis·Ganji Purnachandra NagarajuBassel F El-Rayes
Aug 27, 2014·Seminars in Cell & Developmental Biology·E A Dunlop, A R Tee

❮ Previous
Next ❯

Citations

Feb 6, 2020·Cancers·Luis PalomeroMiquel Angel Pujana
Oct 20, 2020·Frontiers in Medicine·Xixi SongMeiling Jin
Mar 7, 2021·International Journal of Molecular Sciences·Jilly Frances EvansVera P Krymskaya
Jul 30, 2021·Biochemical and Biophysical Research Communications·Ji-Hyun Bae, Jong Hyun Kim
May 6, 2021·American Journal of Respiratory and Critical Care Medicine·Monica Goldklang

❮ Previous
Next ❯

Methods Mentioned

BETA
GTPase
protein folding
xenograft
ubiquitination
nuclear translocation
zymography

Software Mentioned

Adobe Photoshop CC
Prism
ImageJ
GraphPad

Related Concepts

Related Feeds

Adherens Junctions

An adherens junction is defined as a cell junction whose cytoplasmic face is linked to the actin cytoskeleton. They can appear as bands encircling the cell (zonula adherens) or as spots of attachment to the extracellular matrix (adhesion plaques). Adherens junctions uniquely disassemble in uterine epithelial cells to allow the blastocyst to penetrate between epithelial cells. Discover the latest research on adherens junctions here.

Cadherins and Catenins

Cadherins (named for "calcium-dependent adhesion") are a type of cell adhesion molecule (CAM) that is important in the formation of adherens junctions to bind cells with each other. Catenins are a family of proteins found in complexes with cadherin cell adhesion molecules of animal cells: alpha-catenin can bind to β-catenin and can also bind actin. β-catenin binds the cytoplasmic domain of some cadherins. Discover the latest research on cadherins and catenins here.