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SMER28 Attenuates PI3K/mTOR Signaling by Direct Inhibition of PI3K p110 Delta

SMER28 (Small molecule enhancer of Rapamycin 28) is an autophagy-inducing compound functioning by a hitherto unknown mechanism. Here, we confirm its autophagy-inducing effect by assessing classical autophagy-related parameters. Interestingly, we also discovered several additional effects of SMER28,...

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Autores principales: Kirchenwitz, Marco, Stahnke, Stephanie, Prettin, Silvia, Borowiak, Malgorzata, Menke, Laura, Sieben, Christian, Birchmeier, Carmen, Rottner, Klemens, Stradal, Theresia E. B., Steffen, Anika
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9140127/
https://www.ncbi.nlm.nih.gov/pubmed/35626685
http://dx.doi.org/10.3390/cells11101648
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author Kirchenwitz, Marco
Stahnke, Stephanie
Prettin, Silvia
Borowiak, Malgorzata
Menke, Laura
Sieben, Christian
Birchmeier, Carmen
Rottner, Klemens
Stradal, Theresia E. B.
Steffen, Anika
author_facet Kirchenwitz, Marco
Stahnke, Stephanie
Prettin, Silvia
Borowiak, Malgorzata
Menke, Laura
Sieben, Christian
Birchmeier, Carmen
Rottner, Klemens
Stradal, Theresia E. B.
Steffen, Anika
author_sort Kirchenwitz, Marco
collection PubMed
description SMER28 (Small molecule enhancer of Rapamycin 28) is an autophagy-inducing compound functioning by a hitherto unknown mechanism. Here, we confirm its autophagy-inducing effect by assessing classical autophagy-related parameters. Interestingly, we also discovered several additional effects of SMER28, including growth retardation and reduced G1 to S phase progression. Most strikingly, SMER28 treatment led to a complete arrest of receptor tyrosine kinase signaling, and, consequently, growth factor-induced cell scattering and dorsal ruffle formation. This coincided with a dramatic reduction in phosphorylation patterns of PI3K downstream effectors. Consistently, SMER28 directly inhibited PI3Kδ and to a lesser extent p110γ. The biological relevance of our observations was underscored by SMER28 interfering with InlB-mediated host cell entry of Listeria monocytogenes, which requires signaling through the prominent receptor tyrosine kinase c-Met. This effect was signaling-specific, since entry of unrelated, gram-negative Salmonella Typhimurium was not inhibited. Lastly, in B cell lymphoma cells, which predominantly depend on tonic signaling through PI3Kδ, apoptosis upon SMER28 treatment is profound in comparison to non-hematopoietic cells. This indicates SMER28 as a possible drug candidate for the treatment of diseases that derive from aberrant PI3Kδ activity.
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spelling pubmed-91401272022-05-28 SMER28 Attenuates PI3K/mTOR Signaling by Direct Inhibition of PI3K p110 Delta Kirchenwitz, Marco Stahnke, Stephanie Prettin, Silvia Borowiak, Malgorzata Menke, Laura Sieben, Christian Birchmeier, Carmen Rottner, Klemens Stradal, Theresia E. B. Steffen, Anika Cells Article SMER28 (Small molecule enhancer of Rapamycin 28) is an autophagy-inducing compound functioning by a hitherto unknown mechanism. Here, we confirm its autophagy-inducing effect by assessing classical autophagy-related parameters. Interestingly, we also discovered several additional effects of SMER28, including growth retardation and reduced G1 to S phase progression. Most strikingly, SMER28 treatment led to a complete arrest of receptor tyrosine kinase signaling, and, consequently, growth factor-induced cell scattering and dorsal ruffle formation. This coincided with a dramatic reduction in phosphorylation patterns of PI3K downstream effectors. Consistently, SMER28 directly inhibited PI3Kδ and to a lesser extent p110γ. The biological relevance of our observations was underscored by SMER28 interfering with InlB-mediated host cell entry of Listeria monocytogenes, which requires signaling through the prominent receptor tyrosine kinase c-Met. This effect was signaling-specific, since entry of unrelated, gram-negative Salmonella Typhimurium was not inhibited. Lastly, in B cell lymphoma cells, which predominantly depend on tonic signaling through PI3Kδ, apoptosis upon SMER28 treatment is profound in comparison to non-hematopoietic cells. This indicates SMER28 as a possible drug candidate for the treatment of diseases that derive from aberrant PI3Kδ activity. MDPI 2022-05-16 /pmc/articles/PMC9140127/ /pubmed/35626685 http://dx.doi.org/10.3390/cells11101648 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Kirchenwitz, Marco
Stahnke, Stephanie
Prettin, Silvia
Borowiak, Malgorzata
Menke, Laura
Sieben, Christian
Birchmeier, Carmen
Rottner, Klemens
Stradal, Theresia E. B.
Steffen, Anika
SMER28 Attenuates PI3K/mTOR Signaling by Direct Inhibition of PI3K p110 Delta
title SMER28 Attenuates PI3K/mTOR Signaling by Direct Inhibition of PI3K p110 Delta
title_full SMER28 Attenuates PI3K/mTOR Signaling by Direct Inhibition of PI3K p110 Delta
title_fullStr SMER28 Attenuates PI3K/mTOR Signaling by Direct Inhibition of PI3K p110 Delta
title_full_unstemmed SMER28 Attenuates PI3K/mTOR Signaling by Direct Inhibition of PI3K p110 Delta
title_short SMER28 Attenuates PI3K/mTOR Signaling by Direct Inhibition of PI3K p110 Delta
title_sort smer28 attenuates pi3k/mtor signaling by direct inhibition of pi3k p110 delta
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9140127/
https://www.ncbi.nlm.nih.gov/pubmed/35626685
http://dx.doi.org/10.3390/cells11101648
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