ALK inhibition activates LC3B-independent, protective autophagy in EML4-ALK positive lung cancer cells

Abstract ALK inhibitors effectively target EML4-ALK positive non-small cell lung cancer, but their effects are hampered by treatment resistance. In the present study, we asked whether ALK inhibition affects autophagy, and whether this may influence treatment response. Whereas the impact of targeted...

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Autores principales:	Anna M. Schläfli, Igor Tokarchuk, Sarah Parejo, Susanne Jutzi, Sabina Berezowska, Nikolai Engedal, Mario P. Tschan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/36d00b765291419896f093de52d297ab
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spelling	oai:doaj.org-article:36d00b765291419896f093de52d297ab2021-12-02T17:39:18ZALK inhibition activates LC3B-independent, protective autophagy in EML4-ALK positive lung cancer cells10.1038/s41598-021-87966-62045-2322https://doaj.org/article/36d00b765291419896f093de52d297ab2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87966-6https://doaj.org/toc/2045-2322Abstract ALK inhibitors effectively target EML4-ALK positive non-small cell lung cancer, but their effects are hampered by treatment resistance. In the present study, we asked whether ALK inhibition affects autophagy, and whether this may influence treatment response. Whereas the impact of targeted therapies on autophagic activity previously have been assessed by surrogate marker proteins such as LC3B, we here thoroughly examined effects on functional autophagic activity, i.e. on the sequestration and degradation of autophagic cargo, in addition to autophagic markers. Interestingly, the ALK inhibitor Ceritinib decreased mTOR activity and increased GFP-WIPI1 dot formation in H3122 and H2228 EML4-ALK+ lung cancer cells, suggesting autophagy activation. Moreover, an mCherry-EGFP-LC3B based assay indicated elevated LC3B carrier flux upon ALK inhibition. In accordance, autophagic cargo sequestration and long-lived protein degradation significantly increased upon ALK inhibition. Intriguingly, autophagic cargo flux was dependent on VPS34 and ULK1, but not LC3B. Co-treating H3122 cells with Ceritinib and a VPS34 inhibitor or Bafilomycin A1 resulted in reduced cell numbers. Moreover, VPS34 inhibition reduced clonogenic recovery of Ceritinib-treated cells. In summary, our results indicate that ALK inhibition triggers LC3B-independent macroautophagic flux in EML4-ALK+ cells to support cancer cell survival and clonogenic growth.Anna M. SchläfliIgor TokarchukSarah ParejoSusanne JutziSabina BerezowskaNikolai EngedalMario P. TschanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Anna M. Schläfli Igor Tokarchuk Sarah Parejo Susanne Jutzi Sabina Berezowska Nikolai Engedal Mario P. Tschan ALK inhibition activates LC3B-independent, protective autophagy in EML4-ALK positive lung cancer cells
description	Abstract ALK inhibitors effectively target EML4-ALK positive non-small cell lung cancer, but their effects are hampered by treatment resistance. In the present study, we asked whether ALK inhibition affects autophagy, and whether this may influence treatment response. Whereas the impact of targeted therapies on autophagic activity previously have been assessed by surrogate marker proteins such as LC3B, we here thoroughly examined effects on functional autophagic activity, i.e. on the sequestration and degradation of autophagic cargo, in addition to autophagic markers. Interestingly, the ALK inhibitor Ceritinib decreased mTOR activity and increased GFP-WIPI1 dot formation in H3122 and H2228 EML4-ALK+ lung cancer cells, suggesting autophagy activation. Moreover, an mCherry-EGFP-LC3B based assay indicated elevated LC3B carrier flux upon ALK inhibition. In accordance, autophagic cargo sequestration and long-lived protein degradation significantly increased upon ALK inhibition. Intriguingly, autophagic cargo flux was dependent on VPS34 and ULK1, but not LC3B. Co-treating H3122 cells with Ceritinib and a VPS34 inhibitor or Bafilomycin A1 resulted in reduced cell numbers. Moreover, VPS34 inhibition reduced clonogenic recovery of Ceritinib-treated cells. In summary, our results indicate that ALK inhibition triggers LC3B-independent macroautophagic flux in EML4-ALK+ cells to support cancer cell survival and clonogenic growth.
format	article
author	Anna M. Schläfli Igor Tokarchuk Sarah Parejo Susanne Jutzi Sabina Berezowska Nikolai Engedal Mario P. Tschan
author_facet	Anna M. Schläfli Igor Tokarchuk Sarah Parejo Susanne Jutzi Sabina Berezowska Nikolai Engedal Mario P. Tschan
author_sort	Anna M. Schläfli
title	ALK inhibition activates LC3B-independent, protective autophagy in EML4-ALK positive lung cancer cells
title_short	ALK inhibition activates LC3B-independent, protective autophagy in EML4-ALK positive lung cancer cells
title_full	ALK inhibition activates LC3B-independent, protective autophagy in EML4-ALK positive lung cancer cells
title_fullStr	ALK inhibition activates LC3B-independent, protective autophagy in EML4-ALK positive lung cancer cells
title_full_unstemmed	ALK inhibition activates LC3B-independent, protective autophagy in EML4-ALK positive lung cancer cells
title_sort	alk inhibition activates lc3b-independent, protective autophagy in eml4-alk positive lung cancer cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/36d00b765291419896f093de52d297ab
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_version_	1718379815728316416

ALK inhibition activates LC3B-independent, protective autophagy in EML4-ALK positive lung cancer cells

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