mtorc1-mediated translational elongation limits intestinal tumour initiation and growth

Transcription

1 mtorc1-mediated translational elongation limits intestinal tumour initiation and growth Faller, W. J.; Jackson, T. J.; Knight, J. R. P.; Rigdway, R. A.; Jamieson, T.; Jones S. A. K. C.; Radulescu, S.; Huels, D. J.; Myant, K. B.; Dudek, K. M.; Casey, H. A.; Scopelliti, A.; Cordero, J. B.; Vidal, M.; Pende, M.; Ryazanov, A. G.; Sonenberg, N.; Meyuhas, O.; Hall, M. N.; Bushell, M.; Willis, A. E. & Sansom, O. J., Nature 2015, 517, Mathilde Willemin 19 th of May 2015

2 Wnt pathway and APC role APC inactivation is a predisposing event 1 in colorectal cancer. 1 Korinek, V. et al. Cons2tu2ve transcrip2onal ac2va2on by a beta- catenin- Tcf complex in APC2/2 colon carcinoma. Science 275, (1997). 2

3 Overview of mtor pathway To keep in mind : Mammalian target of rapamycin Raptor part of the complex Involve in translation regulation mtor pathway involves in cell proliferation and tumour growth 2 2 Pourdehnad, M. et al. Myc and mtor converge on a common node in protein synthesis control that confers synthe2c lethality in Myc- driven cancers. Proc. Natl Acad. Sci. USA 110, (2013). hlp:// 3

4 Increased phosphorylation of mtor effectors 96h after APC deletion 2015 Macmillan Publishers Limited. All rights reserved 4

5 Regeneration of crypts after a challenge as a model of early stage of intestinal cancer rapamycin treatment and raptor deletion decrease intestinal regeneration and prevent Wnt-driven Proliferation. mtor is required for regeneration process! 2015 Macmillan Publishers Limited. All rights reserved 5

6 Rapamycin treatment and raptor deletion NO effect on normal enterocytes, only cells with high level of wnt activity = APC deleted cells = tumour cells! Therapeutic window? 2015 Macmillan Publishers Limited. All rights reserved 6

7 Prophylactic treatment Rapamycin sufficient to treat?! Yes! Mice remain tumour free! rapamycin treatment prevents tumorigenesis in APC deleted cells! 2015 Macmillan Publishers Limited. All rights reserved 7

8 Chemiotherapeutic treatment Mice are loosing clinical symptoms rapamycin treatment drives the regression of established tumors! 2015 Macmillan Publishers Limited. All rights reserved 8

9 What translational process is affected by rapamycin treatment? decrease number of polysomes : 1) faster elongation 2) reduced initiation 2015 Macmillan Publishers Limited. All rights reserved 9

10 Rate of elongation measurment Harringtonine run off assay increased rate of elongation in APC loss cells Nature Structural & Molecular Biology (2014) Macmillan Publishers Limited. All rights reserved

11 Which mtor effectors are playing a role here? K.O. of 4EBP : no effect (predicted = increasment of regeneration) K.O of S6K : less regeneration observed S6K is acting through Rps6 (= more established effector) or eef2k? Rps6 mutant = const. inactivatif Expected : no regeneration eef2k K.O. = eef2 const. actif Expected : regeneration and Resistance to rapamycin 2015 Macmillan Publishers Limited. All rights reserved 11

12 SUMMARY mtor = important for Wnt signaling pathway in intestine mtor is acting through the mtorc1 - S6K eef2k eef2 axis, non expected! mtor as a strategy to treat early stage of colorectal cancer and to prevent tumour development

13 Questions?! 13

14 Colorectal cancer General epidemiology : - Affects colon or rectum = part of big intestine - Second most deadly cancer in EU new cases and deaths - Risks: age, lifestyle and heredity Source : OMS ( viewed on 17th of May 2015) 14

15 «Wnt/β- catenin signaling pathway upregulates c- Myc expression to promote cell proliferabon of P19 teratocarcinoma cells.» Shuai Zhang, Yi Li, Yuling Wu, Kun Shi,Lujun Bing and Jing Hao * (2012) 15

16 TOR as a sensor of nutrients (aa, glutamine, etc.) or Growth factors (Insulin, IGFs) 16

17 Reference: GJ Browne & CG Proud Eur. J. Biochem. 269: ,

18 Elongation regulation hlps:// phosphoryla2on- of- eef2- inhibits- its- protein- synthesis- act.html 18

19 Initiation regulation hlp:// 19