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Dual Inhibition of Autophagy and PI3K/AKT/MTOR Pathway as a Therapeutic Strategy in Head and Neck Squamous Cell Carcinoma

Genomic analyses of head and neck squamous cell carcinoma (HNSCC) have highlighted alterations in the phosphatidylinositol 3-kinase (PI3K) signaling pathway, presenting a therapeutic target for multiple ongoing clinical trials with PI3K or PI3K/MTOR inhibitors. However, these inhibitors can potentia...

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Autores principales: Bernard, Monique, Cardin, Guillaume B., Cahuzac, Maxime, Ayad, Tareck, Bissada, Eric, Guertin, Louis, Bahig, Houda, Nguyen-Tan, Phuc Felix, Filion, Edith, Ballivy, Olivier, Soulieres, Denis, Rodier, Francis, Christopoulos, Apostolos
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563873/
https://www.ncbi.nlm.nih.gov/pubmed/32825725
http://dx.doi.org/10.3390/cancers12092371
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author Bernard, Monique
Cardin, Guillaume B.
Cahuzac, Maxime
Ayad, Tareck
Bissada, Eric
Guertin, Louis
Bahig, Houda
Nguyen-Tan, Phuc Felix
Filion, Edith
Ballivy, Olivier
Soulieres, Denis
Rodier, Francis
Christopoulos, Apostolos
author_facet Bernard, Monique
Cardin, Guillaume B.
Cahuzac, Maxime
Ayad, Tareck
Bissada, Eric
Guertin, Louis
Bahig, Houda
Nguyen-Tan, Phuc Felix
Filion, Edith
Ballivy, Olivier
Soulieres, Denis
Rodier, Francis
Christopoulos, Apostolos
author_sort Bernard, Monique
collection PubMed
description Genomic analyses of head and neck squamous cell carcinoma (HNSCC) have highlighted alterations in the phosphatidylinositol 3-kinase (PI3K) signaling pathway, presenting a therapeutic target for multiple ongoing clinical trials with PI3K or PI3K/MTOR inhibitors. However, these inhibitors can potentially increase autophagy in HNSCC and indirectly support cancer cell survival. Here, we sought to understand the relationship between the PI3K signaling pathway and autophagy during their dual inhibition in a panel of HNSCC cell lines. We used acridine orange staining, immunoblotting, and tandem sensor Red Fluorescent Protein- Green Fluorescent Protein-, microtubule-associated protein 1 light chain 3 beta (RFP-GFP-LC3B) expression analysis to show that PI3K inhibitors increase autophagosomes in HNSCC cells, but that chloroquine treatment effectively inhibits the autophagy that is induced by PI3K inhibitors. Using the Bliss independence model, we determined that the combination of chloroquine with PI3K inhibitors works in synergy to decrease cancer cell proliferation, independent of the PIK3CA status of the cell line. Our results indicate that a strategy focusing on autophagy inhibition enhances the efficacy of therapeutics already in clinical trials. Our results suggest a broader application for this combination therapy that can be promptly translated to in vivo studies.
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spelling pubmed-75638732020-10-27 Dual Inhibition of Autophagy and PI3K/AKT/MTOR Pathway as a Therapeutic Strategy in Head and Neck Squamous Cell Carcinoma Bernard, Monique Cardin, Guillaume B. Cahuzac, Maxime Ayad, Tareck Bissada, Eric Guertin, Louis Bahig, Houda Nguyen-Tan, Phuc Felix Filion, Edith Ballivy, Olivier Soulieres, Denis Rodier, Francis Christopoulos, Apostolos Cancers (Basel) Article Genomic analyses of head and neck squamous cell carcinoma (HNSCC) have highlighted alterations in the phosphatidylinositol 3-kinase (PI3K) signaling pathway, presenting a therapeutic target for multiple ongoing clinical trials with PI3K or PI3K/MTOR inhibitors. However, these inhibitors can potentially increase autophagy in HNSCC and indirectly support cancer cell survival. Here, we sought to understand the relationship between the PI3K signaling pathway and autophagy during their dual inhibition in a panel of HNSCC cell lines. We used acridine orange staining, immunoblotting, and tandem sensor Red Fluorescent Protein- Green Fluorescent Protein-, microtubule-associated protein 1 light chain 3 beta (RFP-GFP-LC3B) expression analysis to show that PI3K inhibitors increase autophagosomes in HNSCC cells, but that chloroquine treatment effectively inhibits the autophagy that is induced by PI3K inhibitors. Using the Bliss independence model, we determined that the combination of chloroquine with PI3K inhibitors works in synergy to decrease cancer cell proliferation, independent of the PIK3CA status of the cell line. Our results indicate that a strategy focusing on autophagy inhibition enhances the efficacy of therapeutics already in clinical trials. Our results suggest a broader application for this combination therapy that can be promptly translated to in vivo studies. MDPI 2020-08-21 /pmc/articles/PMC7563873/ /pubmed/32825725 http://dx.doi.org/10.3390/cancers12092371 Text en © 2020 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
Bernard, Monique
Cardin, Guillaume B.
Cahuzac, Maxime
Ayad, Tareck
Bissada, Eric
Guertin, Louis
Bahig, Houda
Nguyen-Tan, Phuc Felix
Filion, Edith
Ballivy, Olivier
Soulieres, Denis
Rodier, Francis
Christopoulos, Apostolos
Dual Inhibition of Autophagy and PI3K/AKT/MTOR Pathway as a Therapeutic Strategy in Head and Neck Squamous Cell Carcinoma
title Dual Inhibition of Autophagy and PI3K/AKT/MTOR Pathway as a Therapeutic Strategy in Head and Neck Squamous Cell Carcinoma
title_full Dual Inhibition of Autophagy and PI3K/AKT/MTOR Pathway as a Therapeutic Strategy in Head and Neck Squamous Cell Carcinoma
title_fullStr Dual Inhibition of Autophagy and PI3K/AKT/MTOR Pathway as a Therapeutic Strategy in Head and Neck Squamous Cell Carcinoma
title_full_unstemmed Dual Inhibition of Autophagy and PI3K/AKT/MTOR Pathway as a Therapeutic Strategy in Head and Neck Squamous Cell Carcinoma
title_short Dual Inhibition of Autophagy and PI3K/AKT/MTOR Pathway as a Therapeutic Strategy in Head and Neck Squamous Cell Carcinoma
title_sort dual inhibition of autophagy and pi3k/akt/mtor pathway as a therapeutic strategy in head and neck squamous cell carcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563873/
https://www.ncbi.nlm.nih.gov/pubmed/32825725
http://dx.doi.org/10.3390/cancers12092371
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