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The Oncogene Addiction Switch from NOTCH to PI3K Requires Simultaneous Targeting of NOTCH and PI3K Pathway Inhibition in Glioblastoma

The NOTCH pathway regulates neural stem cells and glioma initiating cells (GICs). However, blocking NOTCH activity with γ-secretase inhibitors (GSIs) fails to alter the growth of GICs, as GSIs seem to be active in only a fraction of GICs lines with constitutive NOTCH activity. Here we report loss of...

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Autores principales: Saito, Norihiko, Hirai, Nozomi, Aoki, Kazuya, Suzuki, Ryo, Fujita, Satoshi, Nakayama, Haruo, Hayashi, Morito, Ito, Keisuke, Sakurai, Takatoshi, Iwabuchi, Satoshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356490/
https://www.ncbi.nlm.nih.gov/pubmed/30669546
http://dx.doi.org/10.3390/cancers11010121
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author Saito, Norihiko
Hirai, Nozomi
Aoki, Kazuya
Suzuki, Ryo
Fujita, Satoshi
Nakayama, Haruo
Hayashi, Morito
Ito, Keisuke
Sakurai, Takatoshi
Iwabuchi, Satoshi
author_facet Saito, Norihiko
Hirai, Nozomi
Aoki, Kazuya
Suzuki, Ryo
Fujita, Satoshi
Nakayama, Haruo
Hayashi, Morito
Ito, Keisuke
Sakurai, Takatoshi
Iwabuchi, Satoshi
author_sort Saito, Norihiko
collection PubMed
description The NOTCH pathway regulates neural stem cells and glioma initiating cells (GICs). However, blocking NOTCH activity with γ-secretase inhibitors (GSIs) fails to alter the growth of GICs, as GSIs seem to be active in only a fraction of GICs lines with constitutive NOTCH activity. Here we report loss of PTEN function as a critical event leading to resistance to NOTCH inhibition, which causes the transfer of oncogene addiction from the NOTCH pathway to the PI3K pathway. Drug cytotoxicity testing of eight GICs showed a differential growth response to GSI, and the GICs were thus stratified into two groups: sensitive and resistant. In the sensitive group, GICs with loss of PTEN function appeared less sensitive to GSI treatment. Here we show that NOTCH regulates PTEN expression and the activity of the PI3K pathway in GICs, as treatment with GSI attenuated the NOTCH pathway and increased PTEN expression. NOTCH regulates PTEN expression via Hes-1, as knockdown of Notch or Hes1 increased expression of PTEN. This novel observation suggests that both pathways must be simultaneously inhibited in order to improve therapeutic efficacy in human glioblastomas (GBMs).
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spelling pubmed-63564902019-02-05 The Oncogene Addiction Switch from NOTCH to PI3K Requires Simultaneous Targeting of NOTCH and PI3K Pathway Inhibition in Glioblastoma Saito, Norihiko Hirai, Nozomi Aoki, Kazuya Suzuki, Ryo Fujita, Satoshi Nakayama, Haruo Hayashi, Morito Ito, Keisuke Sakurai, Takatoshi Iwabuchi, Satoshi Cancers (Basel) Article The NOTCH pathway regulates neural stem cells and glioma initiating cells (GICs). However, blocking NOTCH activity with γ-secretase inhibitors (GSIs) fails to alter the growth of GICs, as GSIs seem to be active in only a fraction of GICs lines with constitutive NOTCH activity. Here we report loss of PTEN function as a critical event leading to resistance to NOTCH inhibition, which causes the transfer of oncogene addiction from the NOTCH pathway to the PI3K pathway. Drug cytotoxicity testing of eight GICs showed a differential growth response to GSI, and the GICs were thus stratified into two groups: sensitive and resistant. In the sensitive group, GICs with loss of PTEN function appeared less sensitive to GSI treatment. Here we show that NOTCH regulates PTEN expression and the activity of the PI3K pathway in GICs, as treatment with GSI attenuated the NOTCH pathway and increased PTEN expression. NOTCH regulates PTEN expression via Hes-1, as knockdown of Notch or Hes1 increased expression of PTEN. This novel observation suggests that both pathways must be simultaneously inhibited in order to improve therapeutic efficacy in human glioblastomas (GBMs). MDPI 2019-01-20 /pmc/articles/PMC6356490/ /pubmed/30669546 http://dx.doi.org/10.3390/cancers11010121 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Saito, Norihiko
Hirai, Nozomi
Aoki, Kazuya
Suzuki, Ryo
Fujita, Satoshi
Nakayama, Haruo
Hayashi, Morito
Ito, Keisuke
Sakurai, Takatoshi
Iwabuchi, Satoshi
The Oncogene Addiction Switch from NOTCH to PI3K Requires Simultaneous Targeting of NOTCH and PI3K Pathway Inhibition in Glioblastoma
title The Oncogene Addiction Switch from NOTCH to PI3K Requires Simultaneous Targeting of NOTCH and PI3K Pathway Inhibition in Glioblastoma
title_full The Oncogene Addiction Switch from NOTCH to PI3K Requires Simultaneous Targeting of NOTCH and PI3K Pathway Inhibition in Glioblastoma
title_fullStr The Oncogene Addiction Switch from NOTCH to PI3K Requires Simultaneous Targeting of NOTCH and PI3K Pathway Inhibition in Glioblastoma
title_full_unstemmed The Oncogene Addiction Switch from NOTCH to PI3K Requires Simultaneous Targeting of NOTCH and PI3K Pathway Inhibition in Glioblastoma
title_short The Oncogene Addiction Switch from NOTCH to PI3K Requires Simultaneous Targeting of NOTCH and PI3K Pathway Inhibition in Glioblastoma
title_sort oncogene addiction switch from notch to pi3k requires simultaneous targeting of notch and pi3k pathway inhibition in glioblastoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356490/
https://www.ncbi.nlm.nih.gov/pubmed/30669546
http://dx.doi.org/10.3390/cancers11010121
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