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Regulating autophagy facilitated therapeutic efficacy of the sonic Hedgehog pathway inhibition on lung adenocarcinoma through GLI2 suppression and ROS production

Lung adenocarcinoma (LUAD), which comprises over 50% of all cases of non-small-cell lung cancer, has a poor prognosis and requires novel therapeutic approaches. The sonic Hedgehog (Shh) pathway, which plays a crucial role in differentiation, proliferation, and survival of cancer cells, is likely to...

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Autores principales: Fan, Jiajun, Zhang, Xuyao, Wang, Shaofei, Chen, Wei, Li, Yubin, Zeng, Xian, Wang, Yichen, Luan, Jingyun, Li, Li, Wang, Ziyu, Sun, Xilin, Shen, Baozhong, Ju, Dianwen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700102/
https://www.ncbi.nlm.nih.gov/pubmed/31427566
http://dx.doi.org/10.1038/s41419-019-1840-6
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author Fan, Jiajun
Zhang, Xuyao
Wang, Shaofei
Chen, Wei
Li, Yubin
Zeng, Xian
Wang, Yichen
Luan, Jingyun
Li, Li
Wang, Ziyu
Sun, Xilin
Shen, Baozhong
Ju, Dianwen
author_facet Fan, Jiajun
Zhang, Xuyao
Wang, Shaofei
Chen, Wei
Li, Yubin
Zeng, Xian
Wang, Yichen
Luan, Jingyun
Li, Li
Wang, Ziyu
Sun, Xilin
Shen, Baozhong
Ju, Dianwen
author_sort Fan, Jiajun
collection PubMed
description Lung adenocarcinoma (LUAD), which comprises over 50% of all cases of non-small-cell lung cancer, has a poor prognosis and requires novel therapeutic approaches. The sonic Hedgehog (Shh) pathway, which plays a crucial role in differentiation, proliferation, and survival of cancer cells, is likely to be activated in LUADs, suggesting the Shh pathway as a potential therapeutic target for LUAD treatment. In this study, we reported that vismodegib, an inhibitor of the Shh pathway, only elicited minor antitumor efficacy in A549 and NCI-H1975 LUAD cells as well as in the xenograft tumors, with overexpressed GLI2 and increased autophagic activity. The aberrant autophagy in LUAD cells was further confirmed by the three main stages of autophagic flux, including the formation of autophagosomes, the fusion of autophagosomes with lysosomes, and degradation of autophagosomes in lysosomes. Furthermore, inhibition of autophagy by siRNA against ATG5 or ATG7 rescued the sensitivity of A549 and NCI-H1975 LUAD cells to vismodegib in vitro. Meanwhile, administration of the pharmaceutical inhibitor of autophagy, chloroquine, contributed to the enhanced anti-LUAD efficacy of vismodegib in vivo, probably through overproduction of ROS, acceleration of apoptosis, and suppression of GLI2 in LUAD tissues. In summary, our research revealed that downregulating autophagy facilitated the anti-LUAD efficacy of the Shh pathway suppression, thus highlighting a potential approach for LUAD therapy via simultaneously targeting the Shh signaling and autophagy pathway.
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spelling pubmed-67001022019-08-20 Regulating autophagy facilitated therapeutic efficacy of the sonic Hedgehog pathway inhibition on lung adenocarcinoma through GLI2 suppression and ROS production Fan, Jiajun Zhang, Xuyao Wang, Shaofei Chen, Wei Li, Yubin Zeng, Xian Wang, Yichen Luan, Jingyun Li, Li Wang, Ziyu Sun, Xilin Shen, Baozhong Ju, Dianwen Cell Death Dis Article Lung adenocarcinoma (LUAD), which comprises over 50% of all cases of non-small-cell lung cancer, has a poor prognosis and requires novel therapeutic approaches. The sonic Hedgehog (Shh) pathway, which plays a crucial role in differentiation, proliferation, and survival of cancer cells, is likely to be activated in LUADs, suggesting the Shh pathway as a potential therapeutic target for LUAD treatment. In this study, we reported that vismodegib, an inhibitor of the Shh pathway, only elicited minor antitumor efficacy in A549 and NCI-H1975 LUAD cells as well as in the xenograft tumors, with overexpressed GLI2 and increased autophagic activity. The aberrant autophagy in LUAD cells was further confirmed by the three main stages of autophagic flux, including the formation of autophagosomes, the fusion of autophagosomes with lysosomes, and degradation of autophagosomes in lysosomes. Furthermore, inhibition of autophagy by siRNA against ATG5 or ATG7 rescued the sensitivity of A549 and NCI-H1975 LUAD cells to vismodegib in vitro. Meanwhile, administration of the pharmaceutical inhibitor of autophagy, chloroquine, contributed to the enhanced anti-LUAD efficacy of vismodegib in vivo, probably through overproduction of ROS, acceleration of apoptosis, and suppression of GLI2 in LUAD tissues. In summary, our research revealed that downregulating autophagy facilitated the anti-LUAD efficacy of the Shh pathway suppression, thus highlighting a potential approach for LUAD therapy via simultaneously targeting the Shh signaling and autophagy pathway. Nature Publishing Group UK 2019-08-19 /pmc/articles/PMC6700102/ /pubmed/31427566 http://dx.doi.org/10.1038/s41419-019-1840-6 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Fan, Jiajun
Zhang, Xuyao
Wang, Shaofei
Chen, Wei
Li, Yubin
Zeng, Xian
Wang, Yichen
Luan, Jingyun
Li, Li
Wang, Ziyu
Sun, Xilin
Shen, Baozhong
Ju, Dianwen
Regulating autophagy facilitated therapeutic efficacy of the sonic Hedgehog pathway inhibition on lung adenocarcinoma through GLI2 suppression and ROS production
title Regulating autophagy facilitated therapeutic efficacy of the sonic Hedgehog pathway inhibition on lung adenocarcinoma through GLI2 suppression and ROS production
title_full Regulating autophagy facilitated therapeutic efficacy of the sonic Hedgehog pathway inhibition on lung adenocarcinoma through GLI2 suppression and ROS production
title_fullStr Regulating autophagy facilitated therapeutic efficacy of the sonic Hedgehog pathway inhibition on lung adenocarcinoma through GLI2 suppression and ROS production
title_full_unstemmed Regulating autophagy facilitated therapeutic efficacy of the sonic Hedgehog pathway inhibition on lung adenocarcinoma through GLI2 suppression and ROS production
title_short Regulating autophagy facilitated therapeutic efficacy of the sonic Hedgehog pathway inhibition on lung adenocarcinoma through GLI2 suppression and ROS production
title_sort regulating autophagy facilitated therapeutic efficacy of the sonic hedgehog pathway inhibition on lung adenocarcinoma through gli2 suppression and ros production
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700102/
https://www.ncbi.nlm.nih.gov/pubmed/31427566
http://dx.doi.org/10.1038/s41419-019-1840-6
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