WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma

TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined...

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Main Authors:	Zhukova, Nataliya, Ramaswamy, Vijay, Remke, Marc, Martin, Dianna C, Castelo-Branco, Pedro, Zhang, Cindy H, Fraser, Michael, Tse, Ken, Poon, Raymond, Shih, David JH, Baskin, Berivan, Ray, Peter N, Bouffet, Eric, Dirks, Peter, von Bueren, Andre O, Pfaff, Elke, Korshunov, Andrey, Jones, David TW, Northcott, Paul A, Kool, Marcel, Pugh, Trevor J, Pomeroy, Scott L, Cho, Yoon-Jae, Pietsch, Torsten, Gessi, Marco, Rutkowski, Stefan, Bognár, Laszlo, Cho, Byung-Kyu, Eberhart, Charles G, Conter, Cecile Faure, Fouladi, Maryam, French, Pim J, Grajkowska, Wieslawa A, Gupta, Nalin, Hauser, Peter, Jabado, Nada, Vasiljevic, Alexandre, Jung, Shin, Kim, Seung-Ki, Klekner, Almos, Kumabe, Toshihiro, Lach, Boleslaw, Leonard, Jeffrey R, Liau, Linda M, Massimi, Luca, Pollack, Ian F, Ra, Young Shin, Rubin, Joshua B, Van Meir, Erwin G, Wang, Kyu-Chang, Weiss, William A, Zitterbart, Karel, Bristow, Robert G, Alman, Benjamin, Hawkins, Cynthia E, Malkin, David, Clifford, Steven C, Pfister, Stefan M, Taylor, Michael D, Tabori, Uri
Format:	Online
Language:	English
Published:	BioMed Central 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297452/

id	pubmed-4297452
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spelling	pubmed-42974522015-02-03 WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma Zhukova, Nataliya Ramaswamy, Vijay Remke, Marc Martin, Dianna C Castelo-Branco, Pedro Zhang, Cindy H Fraser, Michael Tse, Ken Poon, Raymond Shih, David JH Baskin, Berivan Ray, Peter N Bouffet, Eric Dirks, Peter von Bueren, Andre O Pfaff, Elke Korshunov, Andrey Jones, David TW Northcott, Paul A Kool, Marcel Pugh, Trevor J Pomeroy, Scott L Cho, Yoon-Jae Pietsch, Torsten Gessi, Marco Rutkowski, Stefan Bognár, Laszlo Cho, Byung-Kyu Eberhart, Charles G Conter, Cecile Faure Fouladi, Maryam French, Pim J Grajkowska, Wieslawa A Gupta, Nalin Hauser, Peter Jabado, Nada Vasiljevic, Alexandre Jung, Shin Kim, Seung-Ki Klekner, Almos Kumabe, Toshihiro Lach, Boleslaw Leonard, Jeffrey R Liau, Linda M Massimi, Luca Pollack, Ian F Ra, Young Shin Rubin, Joshua B Van Meir, Erwin G Wang, Kyu-Chang Weiss, William A Zitterbart, Karel Bristow, Robert G Alman, Benjamin Hawkins, Cynthia E Malkin, David Clifford, Steven C Pfister, Stefan M Taylor, Michael D Tabori, Uri Research TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6% ± 8.7%, respectively (p < 0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89% ± 2% vs. 57.4% ± 1.8% (p < 0.01)). In contrast, β-catenin mutation sensitized TP53 mutant cells to radiation (p < 0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5% ± 1.5% in lithium treated cells vs. 56.6 ± 3% (p < 0.01)) accompanied by increased number of γH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33% ± 8% for lithium treated cells vs. 27% ± 3% for untreated controls (p = 0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas. BioMed Central 2014-12-24 /pmc/articles/PMC4297452/ /pubmed/25539912 http://dx.doi.org/10.1186/s40478-014-0174-y Text en © Zhukova et al.; licensee BioMed Central. 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Zhukova, Nataliya Ramaswamy, Vijay Remke, Marc Martin, Dianna C Castelo-Branco, Pedro Zhang, Cindy H Fraser, Michael Tse, Ken Poon, Raymond Shih, David JH Baskin, Berivan Ray, Peter N Bouffet, Eric Dirks, Peter von Bueren, Andre O Pfaff, Elke Korshunov, Andrey Jones, David TW Northcott, Paul A Kool, Marcel Pugh, Trevor J Pomeroy, Scott L Cho, Yoon-Jae Pietsch, Torsten Gessi, Marco Rutkowski, Stefan Bognár, Laszlo Cho, Byung-Kyu Eberhart, Charles G Conter, Cecile Faure Fouladi, Maryam French, Pim J Grajkowska, Wieslawa A Gupta, Nalin Hauser, Peter Jabado, Nada Vasiljevic, Alexandre Jung, Shin Kim, Seung-Ki Klekner, Almos Kumabe, Toshihiro Lach, Boleslaw Leonard, Jeffrey R Liau, Linda M Massimi, Luca Pollack, Ian F Ra, Young Shin Rubin, Joshua B Van Meir, Erwin G Wang, Kyu-Chang Weiss, William A Zitterbart, Karel Bristow, Robert G Alman, Benjamin Hawkins, Cynthia E Malkin, David Clifford, Steven C Pfister, Stefan M Taylor, Michael D Tabori, Uri
spellingShingle	Zhukova, Nataliya Ramaswamy, Vijay Remke, Marc Martin, Dianna C Castelo-Branco, Pedro Zhang, Cindy H Fraser, Michael Tse, Ken Poon, Raymond Shih, David JH Baskin, Berivan Ray, Peter N Bouffet, Eric Dirks, Peter von Bueren, Andre O Pfaff, Elke Korshunov, Andrey Jones, David TW Northcott, Paul A Kool, Marcel Pugh, Trevor J Pomeroy, Scott L Cho, Yoon-Jae Pietsch, Torsten Gessi, Marco Rutkowski, Stefan Bognár, Laszlo Cho, Byung-Kyu Eberhart, Charles G Conter, Cecile Faure Fouladi, Maryam French, Pim J Grajkowska, Wieslawa A Gupta, Nalin Hauser, Peter Jabado, Nada Vasiljevic, Alexandre Jung, Shin Kim, Seung-Ki Klekner, Almos Kumabe, Toshihiro Lach, Boleslaw Leonard, Jeffrey R Liau, Linda M Massimi, Luca Pollack, Ian F Ra, Young Shin Rubin, Joshua B Van Meir, Erwin G Wang, Kyu-Chang Weiss, William A Zitterbart, Karel Bristow, Robert G Alman, Benjamin Hawkins, Cynthia E Malkin, David Clifford, Steven C Pfister, Stefan M Taylor, Michael D Tabori, Uri WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma
author_facet	Zhukova, Nataliya Ramaswamy, Vijay Remke, Marc Martin, Dianna C Castelo-Branco, Pedro Zhang, Cindy H Fraser, Michael Tse, Ken Poon, Raymond Shih, David JH Baskin, Berivan Ray, Peter N Bouffet, Eric Dirks, Peter von Bueren, Andre O Pfaff, Elke Korshunov, Andrey Jones, David TW Northcott, Paul A Kool, Marcel Pugh, Trevor J Pomeroy, Scott L Cho, Yoon-Jae Pietsch, Torsten Gessi, Marco Rutkowski, Stefan Bognár, Laszlo Cho, Byung-Kyu Eberhart, Charles G Conter, Cecile Faure Fouladi, Maryam French, Pim J Grajkowska, Wieslawa A Gupta, Nalin Hauser, Peter Jabado, Nada Vasiljevic, Alexandre Jung, Shin Kim, Seung-Ki Klekner, Almos Kumabe, Toshihiro Lach, Boleslaw Leonard, Jeffrey R Liau, Linda M Massimi, Luca Pollack, Ian F Ra, Young Shin Rubin, Joshua B Van Meir, Erwin G Wang, Kyu-Chang Weiss, William A Zitterbart, Karel Bristow, Robert G Alman, Benjamin Hawkins, Cynthia E Malkin, David Clifford, Steven C Pfister, Stefan M Taylor, Michael D Tabori, Uri
author_sort	Zhukova, Nataliya
title	WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma
title_short	WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma
title_full	WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma
title_fullStr	WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma
title_full_unstemmed	WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma
title_sort	wnt activation by lithium abrogates tp53 mutation associated radiation resistance in medulloblastoma
description	TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6% ± 8.7%, respectively (p < 0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89% ± 2% vs. 57.4% ± 1.8% (p < 0.01)). In contrast, β-catenin mutation sensitized TP53 mutant cells to radiation (p < 0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5% ± 1.5% in lithium treated cells vs. 56.6 ± 3% (p < 0.01)) accompanied by increased number of γH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33% ± 8% for lithium treated cells vs. 27% ± 3% for untreated controls (p = 0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.
publisher	BioMed Central
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297452/
_version_	1613177748564475904

WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma

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