p62/SQSTM1 accumulation in squamous cell carcinoma of head and neck predicts sensitivity to phosphatidylinositol 3-kinase pathway inhibitors.

The phosphoinositol-3 kinase (PI3K) pathway is highly dysregulated in squamous cell carcinoma of the head and neck (SCCHN). While inhibitors of the PI3K/AKT pathway are being developed in cancer, their efficacy does not appear to be related to the presence of mutations or amplification in pathway ge...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Wen-Liang Kuo, Marina N Sharifi, Mark W Lingen, Omar Ahmed, Jing Liu, Madhavi Nagilla, Kay F Macleod, Ezra E W Cohen
Formato: article
Lenguaje:EN
Publicado: Public Library of Science (PLoS) 2014
Materias:
R
Q
Acceso en línea:https://doaj.org/article/4fd7eec917de4938b097df865532ae31
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
id oai:doaj.org-article:4fd7eec917de4938b097df865532ae31
record_format dspace
spelling oai:doaj.org-article:4fd7eec917de4938b097df865532ae312021-11-18T08:29:38Zp62/SQSTM1 accumulation in squamous cell carcinoma of head and neck predicts sensitivity to phosphatidylinositol 3-kinase pathway inhibitors.1932-620310.1371/journal.pone.0090171https://doaj.org/article/4fd7eec917de4938b097df865532ae312014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24599075/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203The phosphoinositol-3 kinase (PI3K) pathway is highly dysregulated in squamous cell carcinoma of the head and neck (SCCHN). While inhibitors of the PI3K/AKT pathway are being developed in cancer, their efficacy does not appear to be related to the presence of mutations or amplification in pathway genes. The PI3K pathway is a major regulator of macro-autophagy, an evolutionarily conserved catabolic process that degrades cellular materials to promote cellular homeostasis and survival under stress. Employing a panel of SCCHN cell lines, we observed a significant correlation between the activity of PI3K/AKT inhibitors and their ability to induce autophagy. More specifically, resistance to these inhibitors was associated with accumulation of p62/SQSTM1, a pleotropic protein that is consumed during autophagy, while loss of autophagy was, for the first time, found to be due to silencing of an essential autophagy gene, ATG7. Moreover, modulating ATG7 and p62/SQSTM1 could regulate sensitivity to PI3K/AKT inhibitors, underscoring a mechanistic link between autophagy and drug sensitivity. Analysis of human tissues revealed progressive accumulation of p62/SQSTM1 in a significant proportion of cancer samples compared to normal tissue, suggesting that defective autophagy has relevance to SCCHN. These findings are further validated by analysis of TCGA data confirming homozygous deletion and mRNA down-regulation of ATG7 in 10.0% of SCCHN samples. Taken together, these data indicate that p62/SQSTM1 levels modulate sensitivity to PI3K/AKT inhibitors; cancers vary in their capacity to undergo autophagy through epigenetic modification and, when deficient, accumulate p62/SQSTM1; and expression of autophagy-related proteins may serve as markers for resistance to PI3K/AKT inhibitors in SCCHN.Wen-Liang KuoMarina N SharifiMark W LingenOmar AhmedJing LiuMadhavi NagillaKay F MacleodEzra E W CohenPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 3, p e90171 (2014)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Wen-Liang Kuo
Marina N Sharifi
Mark W Lingen
Omar Ahmed
Jing Liu
Madhavi Nagilla
Kay F Macleod
Ezra E W Cohen
p62/SQSTM1 accumulation in squamous cell carcinoma of head and neck predicts sensitivity to phosphatidylinositol 3-kinase pathway inhibitors.
description The phosphoinositol-3 kinase (PI3K) pathway is highly dysregulated in squamous cell carcinoma of the head and neck (SCCHN). While inhibitors of the PI3K/AKT pathway are being developed in cancer, their efficacy does not appear to be related to the presence of mutations or amplification in pathway genes. The PI3K pathway is a major regulator of macro-autophagy, an evolutionarily conserved catabolic process that degrades cellular materials to promote cellular homeostasis and survival under stress. Employing a panel of SCCHN cell lines, we observed a significant correlation between the activity of PI3K/AKT inhibitors and their ability to induce autophagy. More specifically, resistance to these inhibitors was associated with accumulation of p62/SQSTM1, a pleotropic protein that is consumed during autophagy, while loss of autophagy was, for the first time, found to be due to silencing of an essential autophagy gene, ATG7. Moreover, modulating ATG7 and p62/SQSTM1 could regulate sensitivity to PI3K/AKT inhibitors, underscoring a mechanistic link between autophagy and drug sensitivity. Analysis of human tissues revealed progressive accumulation of p62/SQSTM1 in a significant proportion of cancer samples compared to normal tissue, suggesting that defective autophagy has relevance to SCCHN. These findings are further validated by analysis of TCGA data confirming homozygous deletion and mRNA down-regulation of ATG7 in 10.0% of SCCHN samples. Taken together, these data indicate that p62/SQSTM1 levels modulate sensitivity to PI3K/AKT inhibitors; cancers vary in their capacity to undergo autophagy through epigenetic modification and, when deficient, accumulate p62/SQSTM1; and expression of autophagy-related proteins may serve as markers for resistance to PI3K/AKT inhibitors in SCCHN.
format article
author Wen-Liang Kuo
Marina N Sharifi
Mark W Lingen
Omar Ahmed
Jing Liu
Madhavi Nagilla
Kay F Macleod
Ezra E W Cohen
author_facet Wen-Liang Kuo
Marina N Sharifi
Mark W Lingen
Omar Ahmed
Jing Liu
Madhavi Nagilla
Kay F Macleod
Ezra E W Cohen
author_sort Wen-Liang Kuo
title p62/SQSTM1 accumulation in squamous cell carcinoma of head and neck predicts sensitivity to phosphatidylinositol 3-kinase pathway inhibitors.
title_short p62/SQSTM1 accumulation in squamous cell carcinoma of head and neck predicts sensitivity to phosphatidylinositol 3-kinase pathway inhibitors.
title_full p62/SQSTM1 accumulation in squamous cell carcinoma of head and neck predicts sensitivity to phosphatidylinositol 3-kinase pathway inhibitors.
title_fullStr p62/SQSTM1 accumulation in squamous cell carcinoma of head and neck predicts sensitivity to phosphatidylinositol 3-kinase pathway inhibitors.
title_full_unstemmed p62/SQSTM1 accumulation in squamous cell carcinoma of head and neck predicts sensitivity to phosphatidylinositol 3-kinase pathway inhibitors.
title_sort p62/sqstm1 accumulation in squamous cell carcinoma of head and neck predicts sensitivity to phosphatidylinositol 3-kinase pathway inhibitors.
publisher Public Library of Science (PLoS)
publishDate 2014
url https://doaj.org/article/4fd7eec917de4938b097df865532ae31
work_keys_str_mv AT wenliangkuo p62sqstm1accumulationinsquamouscellcarcinomaofheadandneckpredictssensitivitytophosphatidylinositol3kinasepathwayinhibitors
AT marinansharifi p62sqstm1accumulationinsquamouscellcarcinomaofheadandneckpredictssensitivitytophosphatidylinositol3kinasepathwayinhibitors
AT markwlingen p62sqstm1accumulationinsquamouscellcarcinomaofheadandneckpredictssensitivitytophosphatidylinositol3kinasepathwayinhibitors
AT omarahmed p62sqstm1accumulationinsquamouscellcarcinomaofheadandneckpredictssensitivitytophosphatidylinositol3kinasepathwayinhibitors
AT jingliu p62sqstm1accumulationinsquamouscellcarcinomaofheadandneckpredictssensitivitytophosphatidylinositol3kinasepathwayinhibitors
AT madhavinagilla p62sqstm1accumulationinsquamouscellcarcinomaofheadandneckpredictssensitivitytophosphatidylinositol3kinasepathwayinhibitors
AT kayfmacleod p62sqstm1accumulationinsquamouscellcarcinomaofheadandneckpredictssensitivitytophosphatidylinositol3kinasepathwayinhibitors
AT ezraewcohen p62sqstm1accumulationinsquamouscellcarcinomaofheadandneckpredictssensitivitytophosphatidylinositol3kinasepathwayinhibitors
_version_ 1718421738050551808